owencqueen/cgbench_data huggingface dataset:
Gene: ANO5 (HGNC:27337)
Evidence Code: PVS1 — Original ACMG Summary
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Caveats:
 • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
 • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
 • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
 • Use caution in the presence of multiple transcripts.
Gene: ANO5 (HGNC:27337)
Evidence Code: PVS1 — Very Strong
Modification Type: General recommendation,Gene-specific
Please see attached 
ANO5
 PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.
Gene: ANO5 (HGNC:27337)
Evidence Code: PVS1 — Strong
Modification Type: General recommendation,Gene-specific,Strength
Please see attached 
ANO5
 PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.
Gene: ANO5 (HGNC:27337)
Evidence Code: PVS1 — Moderate
Modification Type: General recommendation,Gene-specific,Strength
Please see attached 
ANO5
 PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.
Gene: ANO5 (HGNC:27337)
Evidence Code: PVS1 — Supporting
Modification Type: General recommendation,Gene-specific,Strength
Please see attached 
ANO5
 PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.
Gene: ANO5 (HGNC:27337)
Evidence Code: PS1 — Original ACMG Summary
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Example: Val->Leu caused by either G>C or G>T in the same codon.
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Gene: ANO5 (HGNC:27337)
Evidence Code: PS1 — Strong
Modification Type: Disease-specific,General recommendation
For missense variants for which the amino acid change is the expected mechanism of disease, apply at Strong for 1 pathogenic or 2 likely pathogenic variants resulting in the same amino acid change. The likely pathogenic or pathogenic variant(s) must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant(s) resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.


For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 


For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).
Gene: ANO5 (HGNC:27337)
Evidence Code: PS1 — Moderate
Modification Type: Disease-specific,General recommendation,Strength
For missense variants for which the amino acid change is the expected mechanism of disease, apply at Moderate for 1 likely pathogenic variant resulting in the same amino acid change. The likely pathogenic variant must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.


For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 


For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).
Gene: ANO5 (HGNC:27337)
Evidence Code: PS1 — Supporting
Modification Type: General recommendation,Strength
For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).
Gene: ANO5 (HGNC:27337)
Evidence Code: PS2 — Original ACMG Summary
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Gene: ANO5 (HGNC:27337)
Evidence Code: PS2 — Very Strong
Modification Type: Disease-specific,General recommendation,Strength
Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. ≥ 4 pts is required to apply PS2 at Very Strong.
Gene: ANO5 (HGNC:27337)
Evidence Code: PS2 — Strong
Modification Type: Disease-specific,General recommendation
Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2 should be applied for ≥ 2 pts but < 4 pts.
Gene: ANO5 (HGNC:27337)
Evidence Code: PS2 — Moderate
Modification Type: Disease-specific,General recommendation,Strength
Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Moderate should be applied for ≥ 1 pt but < 2 pts.
Gene: ANO5 (HGNC:27337)
Evidence Code: PS2 — Supporting
Modification Type: Disease-specific,General recommendation,Strength
Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Supporting should be applied for ≥ 0.5 pts but < 1 pt.
Gene: ANO5 (HGNC:27337)
Evidence Code: PS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
Gene: ANO5 (HGNC:27337)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific,General recommendation
Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3 at Strong for a variant-specific animal model that meets all of the following conditions, regardless of species: 




signs of myopathy or dystrophy are present in skeletal muscle 


an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)


behavioral signs of muscle weakness


progression over time




For 
ANO5
, functional studies in heterologous systems are hard to conduct and rare in the literature. Therefore, PS3 is not applicable at this time for 
in vitro
 assays for variants in 
ANO5
. 


For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).


Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.
Gene: ANO5 (HGNC:27337)
Evidence Code: PS3 — Moderate
Modification Type: Disease-specific,General recommendation,Gene-specific,Strength
Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3_Moderate for a variant-specific animal model that meets all of the following conditions, regardless of species: 




signs of myopathy or dystrophy are present in skeletal muscle 


an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)




For 
ANO5
, functional studies in heterologous systems are hard to conduct and rare in the literature. Therefore, PS3 is not applicable at this time for 
in vitro
 assays for variants in 
ANO5
. 


For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).


Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.
Gene: ANO5 (HGNC:27337)
Evidence Code: PS3 — Supporting
Modification Type: Disease-specific,General recommendation,Gene-specific,Strength
For 
ANO5
, functional studies in heterologous systems are hard to conduct and rare in the literature. Therefore, PS3 is not applicable at this time for 
in vitro
 assays for variants in 
ANO5
. 


For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).


Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.
Gene: ANO5 (HGNC:27337)
Evidence Code: PS4 — Original ACMG Summary
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.
Gene: ANO5 (HGNC:27337)
Evidence Code: PS4 — Strong
Modification Type: Clarification
Use without disease-specific modification if case-control studies are available. 
While case-control studies could potentially be considered for a few pathogenic variants with high minor allele frequency, the VCEP is unaware of any such studies being conducted for 
ANO5
. Any case-control study would require careful selection of an appropriate control population given the potential for late onset and mild disease.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM1 — Original ACMG Summary
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM2 — Original ACMG Summary
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Caveat: Population data for indels may be poorly called by next generation sequencing.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM2 — Supporting
Modification Type: Disease-specific,Strength
Apply if the Grpmax alternate allele frequency / upper bound of the 95% confidence interval (95% CI) of the Grpmax alternate allele frequency in gnomAD is <0.0001. 




If only 1 or 2 alternate alleles are reported in the Grpmax population, apply if the Grpmax alternate allele frequency is <0.0001. 


If at least 3 alternate alleles are reported in the Grpmax population, apply if the upper bound of the 95% CI of the Grpmax alternate allele frequency is <0.0001.




Grpmax refers to the gnomAD subpopulation with the highest alternate allele frequency. Use large, non-bottlenecked genetic ancestry groups for the Grpmax; avoid using the Amish, Ashkenazi Jewish, European Finnish, Remaining, or Middle Eastern (genomes).


The upper bound of the 95% CI must be calculated using the exome or genome allele numbers and counts from gnomAD. Confidence interval tools, such as Confit-de-MAF (
https://www.genecalculators.net/confit-de-maf.html
), can be used.


When comparing different versions of gnomAD for the variant frequency, use the allele count from the version with the largest allele number. 


For larger deletions or duplications that may not be well represented in gnomAD (e.g., single- or multi-exon events), also confirm the variant is not common in gnomAD SVs, gnomAD CNVs, or the Database of Genomic Variants (DGV) (
https://dgv.tcag.ca/dgv/app/home
).
Gene: ANO5 (HGNC:27337)
Evidence Code: PM3 — Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM3 — Very Strong
Modification Type: Disease-specific,General recommendation,Strength
Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). ≥ 4 pts is required to apply PM3 at Very Strong.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM3 — Strong
Modification Type: Disease-specific,General recommendation,Strength
Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Strong should be applied for ≥ 2 pts but < 4 pts.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM3 — Moderate
Modification Type: Disease-specific,General recommendation
Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3 (Moderate) should be applied for ≥ 1 pt but < 2 pts.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM3 — Supporting
Modification Type: Disease-specific,General recommendation,Strength
Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Supporting should be applied for ≥ 0.5 pts but < 1 pt.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM4 — Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM4 — Moderate
Modification Type: No change
Use as is, regardless of the length of the in-frame insertion or deletion.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM5 — Original ACMG Summary
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Example: Arg156His is pathogenic; now you observe Arg156Cys.
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM5 — Strong
Modification Type: Disease-specific,Strength
Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Strong for 2 pathogenic or 3 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.


PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM5 — Moderate
Modification Type: Disease-specific
Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Moderate for 1 pathogenic or 2 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.


PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM5 — Supporting
Modification Type: Disease-specific,Strength
Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant resulting in the same amino acid change. Apply at Supporting for 1 likely pathogenic variant resulting in a different amino acid change at the same residue as the variant under curation.


PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM6 — Strong
Modification Type: Disease-specific,General recommendation,Strength
Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Strong should be applied for ≥ 2 pts but < 4 pts.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM6 — Moderate
Modification Type: Disease-specific,General recommendation
Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6 should be applied for ≥ 1 pt but < 2 pts.
Gene: ANO5 (HGNC:27337)
Evidence Code: PM6 — Supporting
Modification Type: Disease-specific,General recommendation,Strength
Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Supporting should be applied for ≥ 0.5 pts but < 1 pt.
Gene: ANO5 (HGNC:27337)
Evidence Code: PP1 — Original ACMG Summary
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Note: May be used as stronger evidence with increasing segregation data.
Gene: ANO5 (HGNC:27337)
Evidence Code: PP1 — Strong
Modification Type: Disease-specific,Strength
Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Strong for 3 affected segregations (in addition to proband) across ≥2 families. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).
Gene: ANO5 (HGNC:27337)
Evidence Code: PP1 — Moderate
Modification Type: Disease-specific,Strength
Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Moderate for 2 affected segregations (in addition to proband; may be from a single family). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).
Gene: ANO5 (HGNC:27337)
Evidence Code: PP1 — Supporting
Modification Type: Disease-specific
Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1 (Supporting) for 1 affected segregation (in addition to proband). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).
Gene: ANO5 (HGNC:27337)
Evidence Code: PP2 — Original ACMG Summary
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Gene: ANO5 (HGNC:27337)
Evidence Code: PP3 — Original ACMG Summary
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.
Gene: ANO5 (HGNC:27337)
Evidence Code: PP3 — Supporting
Modification Type: Disease-specific
For missense variants, use REVEL with a score ≥0.7. 


For variants that may affect splicing, use SpliceAI with a score ≥0.5.