owencqueen/cgbench_data huggingface dataset:
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: PVS1 — Very Strong
Modification Type: None
Loss of function is a known mechanism of disease for Creatine Transporter Deficiency.


Specifications are based on the decision tree as outlined in Tayoun etal, 2018 (Hum Mutat. 2018 Nov;39(11):1517-1524; PMID: 30192042) SLC6A8: PVS1, at appropriate strength, is applicable as described in Abou Tayoun et al, 2018 (PMID: 30192042)
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: PS1 — Strong
Modification Type: None
PS1 is applicable as described.
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: PS2 — Strong
Modification Type: Disease-specific,None
Note: Confirmation of paternity in females only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.


X-linked disorder. Only maternity needs to be confirmed.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PS2 — Moderate
Modification Type: Disease-specific,Strength
Newly hemizygous male with the variant identified de novo in the mother with no family history of other affected males.
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific
RT-PCR evidence of mis-splicing for non-canonical intronic variants.


For non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PS3 — Supporting
Modification Type: Disease-specific
Creatine transport activity <10% wild type with less than or equal to 125uM creatine used in SLC6A8 deficient fibroblasts


RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.
For non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts.
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: PS4 — Very Strong
Modification Type: Strength
4 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.


Variant must meet PM2_Supporting criterion for PS4 to apply.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PS4 — Strong
Modification Type: Disease-specific
3 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.


Variant must meet PM2_Supporting criterion for PS4 to apply.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PS4 — Moderate
Modification Type: Strength
2 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.


Variant must meet PM2_Supporting criterion for PS4 to apply.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PS4 — Supporting
Modification Type: Strength
One independent male proband in addition to any proband used for PP4.


Variant must meet PM2_Supporting criterion for PS4 to apply.
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: PM2 — Supporting
Modification Type: Disease-specific
Absent/rare from controls in an ethnically-matched cohort population sample. Threshold: <0.00002 (0.002%) AND 0 hemizygotes in gnomAD.
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: PM4 — Moderate
Modification Type: None
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
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.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PM5 — Supporting
Modification Type: Strength
Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PM6 — Moderate
Modification Type: No change
Variant identified as de novo in an affected male with the mother negative for the variant but maternity not confirmed.
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: PP1 — Strong
Modification Type: Strength
3 affected segregations + 0 unaffected segregations OR


2 affected segregations + 3 unaffected segregations
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PP1 — Moderate
Modification Type: Strength
2 affected segregations + 0 unaffected segregations.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PP1 — Supporting
Modification Type: Disease-specific
1 affected family member + 3 unaffected segregations.
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: PP3 — Supporting
Modification Type: None
REVEL score >0.75 for missense variants


In frame deletion or insertion predicted deleterious by PROVEAN, MutPred indel, and MutationTaster.


Predicted impact on splicing by SpliceAI and varSEAK.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PP4 — Strong
Modification Type: Disease-specific
4 or more points based on combinations of the following. 




Elevated urine creatine/creatinine ratio on one occasion (1 point)


Elevated urine creatine/creatinine ratio on more than one occasion (2 points)


Significantly decreased creatine peak, with absent guanidinoacetate peak, if reported (3 points)


Deficient creatine uptake in cultured fibroblasts (<10% of normal with <125uM creatine) (3 points)




Additional specifications:




Two or more data types are required for PP4_Strong.


An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.


Variant must meet PM2_Supporting for PP4 to apply at any strength.


For PP4 to be applied at strong, full SLC6A8 gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PP4 — Moderate
Modification Type: Strength
3 or more points based on: 




Elevated urine creatine/creatinine ratio on one occasion (1 point)


Elevated urine creatine/creatinine ratio on more than one occasion (2 points)


Significantly decreased creatine peak, with absent guanidinoacetate peak, if reported (3 points)


Deficient creatine uptake in cultured fibroblasts (<10% of normal with <125uM creatine) (3 points)




Additional specifications:




Two or more data types are recommended for PP4_Moderate.


An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.


Variant must meet PM2_Supporting for PP4 to apply at any strength.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific
1-2 or more points based on: 




Elevated urine creatine/creatinine ratio on one occasion (1 point)


Elevated urine creatine/creatinine ratio on more than one occasion (2 points)




Additional specifications:




An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.


Variant must meet PM2_Supporting for PP4 to apply at any strength.
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Allele frequency >0.0020 (0.2%) OR ≥10 hemizygotes in gnomAD
Gene: SLC6A8 (HGNC:11055)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Allele frequency > 0.0002 (0.02%) OR ≥ 5 hemizygotes in gnomAD
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: BS2 — Strong
Modification Type: None
Observed in the homozygous state in a healthy adult
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: BS3 — Supporting
Modification Type: Disease-specific,Strength
Creatine transport assay demonstrating ≥50% normal transport activity using physiological creatine concentrations (≤125μM creatine).


RT-PCR evidence demonstrating no observable effect of splicing.


Expression assay demonstrating wild type transcript levels
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: BS4 — Strong
Modification Type: None
Lack of segregation in affected members of a family.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
Evidence Code: BP4 — Supporting
Modification Type: None
REVEL score <0.2 for missense variants


In frame deletion or insertion predicted benign by PROVEAN, MutPred indel, and MutationTaster.


No predicted impact on splicing by SpliceAI and varSEAK.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: SLC6A8 (HGNC:11055)
Evidence Code: BP5 — Supporting
Modification Type: None
Variant found in a case with an alternate molecular basis for disease.
BP5 applicable as described; the case must have specific features of creatine transporter deficiency, such as low creatine on brain magnetic resonance spectroscopy, or elevated urine creatine in order to apply this criterion. Presence of developmental delay and seizures is not sufficient.
Gene: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
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: SLC6A8 (HGNC:11055)
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.