owencqueen/cgbench_data huggingface dataset:
Gene: CDKL5 (HGNC:11411)
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: CDKL5 (HGNC:11411)
Evidence Code: PVS1 — Very Strong
Modification Type: Disease-specific
Null variant in a gene where loss of function is a known mechanism of disease.




Use as defined by ClinGen SVI working group (PMID:30192042).


Do not use PVS1 for truncating variants in CDKL5 Cterminus (exons 19-21, or after p.P904) when using the historically used transcript (NM_003159.2). PVS1 is applicable up to p.R948 when using the major brain isoform which has an alternative C-terminus (NM_001323289.2), for canonical splice site variants predicted to result in an out-of-frame product, for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exons 7, 10, 13), and for the non-coding CDKL5 exon (exon 1).
Gene: CDKL5 (HGNC:11411)
Evidence Code: PVS1 — Moderate
Modification Type: Disease-specific
Null variant in a gene where loss of function is a known mechanism of disease.




PVS1_Moderate is applicable for any truncating variant distal of p.R948 (when using the major brain isoform, NM_001323289.2) and for canonical splice site variants that flank exon 17 (in-frame exon).
Gene: CDKL5 (HGNC:11411)
Evidence Code: PVS1 — Supporting
Modification Type: Disease-specific
Null variant in a gene where loss of function is a known mechanism of disease.




PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.
Gene: CDKL5 (HGNC:11411)
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: CDKL5 (HGNC:11411)
Evidence Code: PS1 — Strong
Modification Type: None
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Gene: CDKL5 (HGNC:11411)
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: CDKL5 (HGNC:11411)
Evidence Code: PS2 — Very Strong
Modification Type: Strength
De novo (maternity and paternity confirmed) in a patient with the disease and no family history.




≥2 independent occurrences of PS2.


≥2 independent occurrences of PM6 and one occurrence of PS2.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PS2 — Strong
Modification Type: None
De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
Gene: CDKL5 (HGNC:11411)
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: CDKL5 (HGNC:11411)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific
Well-established in vitro or in vivo functional studies supportive of a damaging effect.




RNA studies that demonstrate abnormal splicing and an out-offrame transcript.


Do not use for canonical splice site variants and when PVS1 is used.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PS3 — Supporting
Modification Type: Disease-specific
Well-established in vitro or in vivo functional studies supportive of a damaging effect.




RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).


See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.
Gene: CDKL5 (HGNC:11411)
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: CDKL5 (HGNC:11411)
Evidence Code: PS4 — Strong
Modification Type: Strength
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.




5+ observations.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PS4 — Moderate
Modification Type: Strength
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.




3-4 observations.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PS4 — Supporting
Modification Type: Strength
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.




Use for 2nd independent occurrence.
Gene: CDKL5 (HGNC:11411)
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: CDKL5 (HGNC:11411)
Evidence Code: PM1 — Moderate
Modification Type: Disease-specific
Located in a mutational hot spot and/or critical and well-established functional domain.




(ATP binding region: aa 19-43; TEY phosphorylation site: aa 169-171).
Gene: CDKL5 (HGNC:11411)
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: CDKL5 (HGNC:11411)
Evidence Code: PM2 — Supporting
Modification Type: Strength
Absent/rare from controls in an ethnically-matched cohort population sample.




Use if absent, zero observations in control databases.
Gene: CDKL5 (HGNC:11411)
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: CDKL5 (HGNC:11411)
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: CDKL5 (HGNC:11411)
Evidence Code: PM4 — Moderate
Modification Type: Disease-specific
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.




Do not use for in-frame deletions/insertions in CDKL5 C-terminus (exons 19-21, or after p.904) when using the NM_003159.2 transcript.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PM4 — Supporting
Modification Type: Strength
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.




Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).
Gene: CDKL5 (HGNC:11411)
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: CDKL5 (HGNC:11411)
Evidence Code: PM5 — Strong
Modification Type: Strength
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.




≥2 different missense changes affecting the amino acid residue.


Do not apply PM1 in these situations.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PM5 — Moderate
Modification Type: None
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.




Applicable to all genes as written.


A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PM6 — Very Strong
Modification Type: Strength
Confirmed de novo without confirmation of paternity and maternity.




≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PM6 — Strong
Modification Type: Strength
Confirmed de novo without confirmation of paternity and maternity.




≥2 independent occurrences of PM6.


Evidence from literature must be fully evaluated to support independent events.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PM6 — Moderate
Modification Type: None
Confirmed de novo without confirmation of paternity and maternity.
Gene: CDKL5 (HGNC:11411)
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: CDKL5 (HGNC:11411)
Evidence Code: PP1 — Strong
Modification Type: Strength
Co-segregation with disease in multiple affected family members.




≥5 informative meiosis.


Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).
Gene: CDKL5 (HGNC:11411)
Evidence Code: PP1 — Moderate
Modification Type: Strength
Co-segregation with disease in multiple affected family members.




3-4 informative meiosis.


Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).
Gene: CDKL5 (HGNC:11411)
Evidence Code: PP1 — Supporting
Modification Type: Strength
Co-segregation with disease in multiple affected family members.




2 informative meiosis.


Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).
Gene: CDKL5 (HGNC:11411)
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: CDKL5 (HGNC:11411)
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: CDKL5 (HGNC:11411)
Evidence Code: PP3 — Supporting
Modification Type: None
Multiple lines of computational evidence support a deleterious effect on the gene or gene product.




For missense variants use REVEL with a score ≥ 0.75.


For splice site variants use MaxEntScan, NNSPLICE and HumanSplicingFinder when the majority of the predictions program support splicing alteration.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific
Phenotype specific for disease with single genetic etiology.




See gene specific clinical phenotype guidelines.
Gene: CDKL5 (HGNC:11411)
Evidence Code: PP5 — Original ACMG Summary
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Allele frequency above 0.05%.




Use large population databases (i.e. gnomAD).


Use if variant is present at ≥0.0003 (0.03%) in any sub-population.


Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Allele frequency greater than expected for disease (0.025%).




Use large population databases (i.e. gnomAD).


Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.


Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BS2 — Original ACMG Summary
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BS2 — Strong
Modification Type: Strength
Observed in the heterozygous/hemizygous state in a healthy adult.




2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).
Gene: CDKL5 (HGNC:11411)
Evidence Code: BS2 — Supporting
Modification Type: Strength
Observed in the heterozygous/hemizygous state in a healthy adult.




1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).
Gene: CDKL5 (HGNC:11411)
Evidence Code: BS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BS3 — Strong
Modification Type: Disease-specific
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.




RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.


Not applicable for these genes for other functional studies (see tables for other accepted functional studies).
Gene: CDKL5 (HGNC:11411)
Evidence Code: BS4 — Original ACMG Summary
Lack of segregation in affected members of a family.
Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BS4 — Strong
Modification Type: Strength
Lack of segregation in affected members of a family.




Absent in a similarly affected family member, when seen in two or more families.


Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BS4 — Supporting
Modification Type: Strength
Lack of segregation in affected members of a family.




Absent in a similarly affected family member.


Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP2 — Original ACMG Summary
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP2 — Supporting
Modification Type: Disease-specific
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.




BP2 is not applicable for SLC9A6, UBE3A and CDKL5 for in trans state.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP4 — Original ACMG Summary
Multiple lines of computational evidence suggest no impact on 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 cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP4 — Supporting
Modification Type: None
Multiple lines of computational evidence suggest no impact on gene or gene product.




For missense variants use REVEL with a score ≤ 0.15.
 For splice site variants use MaxEntScan, NNSPLICE and HumanSplicingFinder when the majority of the predictions program support no splicing alteration.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP5 — Strong
Modification Type: Strength
Variant found in a case with an alternate molecular basis for disease.




≥3 cases with alternate molecular basis for disease.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP5 — Supporting
Modification Type: Disease-specific
Variant found in a case with an alternate molecular basis for disease.




Do not apply for any gene if variant is de novo.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP6 — Original ACMG Summary
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP7 — Original ACMG Summary
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Gene: CDKL5 (HGNC:11411)
Evidence Code: BP7 — Supporting
Modification Type: None
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.




Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.
Gene: FOXG1 (HGNC:3811)
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: FOXG1 (HGNC:3811)
Evidence Code: PVS1 — Very Strong
Modification Type: Disease-specific
Null variant in a gene where loss of function is a known mechanism of disease.




Use as defined by ClinGen SVI working group (PMID:30192042).


PVS1 is applicable up to p.S468.
Gene: FOXG1 (HGNC:3811)
Evidence Code: PVS1 — Strong
Null variant in a gene where loss of function is a known mechanism of disease.




PVS1_Strong is applicable for any truncating variant from p.S469 to p.Q480.
Gene: FOXG1 (HGNC:3811)
Evidence Code: PVS1 — Moderate
Modification Type: Disease-specific
Null variant in a gene where loss of function is a known mechanism of disease.




PVS1_Moderate is applicable for any truncating variant distal of p.Q480.
Gene: FOXG1 (HGNC:3811)
Evidence Code: PVS1 — Supporting
Modification Type: Disease-specific
Null variant in a gene where loss of function is a known mechanism of disease.




PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.
Gene: FOXG1 (HGNC:3811)
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: FOXG1 (HGNC:3811)
Evidence Code: PS1 — Strong
Modification Type: None
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Gene: FOXG1 (HGNC:3811)
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: FOXG1 (HGNC:3811)
Evidence Code: PS2 — Very Strong
Modification Type: Strength
De novo (maternity and paternity confirmed) in a patient with the disease and no family history.




≥2 independent occurrences of PS2.


≥2 independent occurrences of PM6 and one occurrence of PS2.
Gene: FOXG1 (HGNC:3811)
Evidence Code: PS2 — Strong
Modification Type: None
De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
Gene: FOXG1 (HGNC:3811)
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: FOXG1 (HGNC:3811)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific
Well-established in vitro or in vivo functional studies supportive of a damaging effect.




RNA studies that demonstrate abnormal splicing and an out-offrame transcript.


Do not use for canonical splice site variants and when PVS1 is used.
Gene: FOXG1 (HGNC:3811)
Evidence Code: PS3 — Supporting
Modification Type: Disease-specific
Well-established in vitro or in vivo functional studies supportive of a damaging effect.




RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).


See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.
Gene: FOXG1 (HGNC:3811)
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: FOXG1 (HGNC:3811)
Evidence Code: PS4 — Strong
Modification Type: Strength
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.




5+ observations.
Gene: FOXG1 (HGNC:3811)
Evidence Code: PS4 — Moderate
Modification Type: Strength
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.




3-4 observations.