owencqueen/cgbench_data huggingface dataset:
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: PVS1 — Very Strong
Modification Type: No change
Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.


Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. 


In-frame exons: 1, 7, 8, 12, 17, 25


Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26


Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.


For splice region variants, this criterion should not be applied with PP3.
Gene: SCN2A (HGNC:10588)
Evidence Code: PVS1 — Strong
Modification Type: No change
Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.


Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591.


In-frame exons: 1, 7, 8, 12, 17, 25


Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26


Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.


For splice region variants, this criterion should not be applied with PP3.
Gene: SCN2A (HGNC:10588)
Evidence Code: PVS1 — Moderate
Modification Type: No change
Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.


Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. 


In-frame exons: 1, 7, 8, 12, 17, 25


Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26


Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.


For splice region variants, this criterion should not be applied with PP3.
Gene: SCN2A (HGNC:10588)
Evidence Code: PVS1 — Supporting
Modification Type: No change
Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.


Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. 


In-frame exons: 1, 7, 8, 12, 17, 25


Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26


Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.


For splice region variants, this criterion should not be applied with PP3.
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: PS1 — Strong
Modification Type: Gene-specific
Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).




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.


>1
 Identical amino acid change in paralogous gene previously established as 
Pathogenic or Likely Pathogenic
, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.




Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). 




PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1_Variants impacting splicing").
Gene: SCN2A (HGNC:10588)
Evidence Code: PS1 — Moderate
Modification Type: Gene-specific,Strength
Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).




Same amino acid change as a previously established 
Likely Pathogenic
 variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.




Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).




PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1_Variants impacting splicing").
Gene: SCN2A (HGNC:10588)
Evidence Code: PS1 — Supporting
Modification Type: Disease-specific,Strength
Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).




A single identical amino acid change in a paralogous gene previously established as 
Pathogenic or Likely Pathogenic
, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.




Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).




PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1_Variants impacting splicing").
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: PS2 — Very Strong
Modification Type: Disease-specific,Strength
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
4 points
 will arrive at 
Very Strong
. 




Complex Neurodevelopmental Disorder: 1 points


Other phenotypes not consistent w/neurodevelopmental disorder: 0 points




Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Gene: SCN2A (HGNC:10588)
Evidence Code: PS2 — Strong
Modification Type: Disease-specific,Strength
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
2 points
 will arrive at 
Strong
. 




Complex Neurodevelopmental Disorder: 1 points


Other phenotypes not consistent w/neurodevelopmental disorder: 0 points




Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Gene: SCN2A (HGNC:10588)
Evidence Code: PS2 — Moderate
Modification Type: Disease-specific,Strength
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
1 point
 will arrive at 
Moderate
. 




Complex Neurodevelopmental Disorder: 1 points


Other phenotypes not consistent w/neurodevelopmental disorder: 0 points




Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Gene: SCN2A (HGNC:10588)
Evidence Code: PS2 — Supporting
Modification Type: Disease-specific,Strength
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
0.5 points
 will arrive at 
Supporting
. 




Complex Neurodevelopmental Disorder: 1 points


Other phenotypes not consistent w/neurodevelopmental disorder: 0 points




Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific,Gene-specific
In patch clamping experiments: Peak current as defined by FENICS ontology (
https://bioportal.bioontology.org/ontologies/FENICS
) is less than or equal to 72.7% of wildtype.


In patch clamping experiments: Persistent current as defined by FENICS ontology (
https://bioportal.bioontology.org/ontologies/FENICS
) is greater than or equal to 135% of wildtype.


In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
https://bioportal.bioontology.org/ontologies/FENICS
) is shifted by at least 2.2 mV (absolute value).


In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
https://bioportal.bioontology.org/ontologies/FENICS
) is shifted by at least 4.1 mV (absolute value).


Mouse knock-in model displays spontaneous seizures.
Gene: SCN2A (HGNC:10588)
Evidence Code: PS3 — Moderate
Modification Type: Gene-specific,Strength
In patch clamping experiments: Peak current as defined by FENICS ontology (
https://bioportal.bioontology.org/ontologies/FENICS
) is less than or equal to 80.6% of wildtype.


In patch clamping experiments: Persistent current as defined by FENICS ontology (
https://bioportal.bioontology.org/ontologies/FENICS
) is greater than or equal to 125% of wildtype.


In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
https://bioportal.bioontology.org/ontologies/FENICS
) is shifted by at least 2.1 mV (absolute value).


In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
https://bioportal.bioontology.org/ontologies/FENICS
) is shifted by at least 3.0 mV (absolute value).


Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies
Gene: SCN2A (HGNC:10588)
Evidence Code: PS3 — Supporting
Modification Type: Gene-specific,Strength
Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: PS4 — Very Strong
Modification Type: Disease-specific,Gene-specific,Strength
Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
16+ points
 will arrive at 
Very Strong
. 




Complex Neurodevelopmental Disorder: 1 points


Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
Gene: SCN2A (HGNC:10588)
Evidence Code: PS4 — Strong
Modification Type: Disease-specific,Gene-specific
Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
4 - 15.5 points
 will arrive at 
Strong
. 




Complex Neurodevelopmental Disorder: 1 points


Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
Gene: SCN2A (HGNC:10588)
Evidence Code: PS4 — Moderate
Modification Type: Disease-specific,Gene-specific,Strength
Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
2 - 3.5 points
 will arrive at 
Moderate
. 




Complex Neurodevelopmental Disorder: 1 points


Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
Gene: SCN2A (HGNC:10588)
Evidence Code: PS4 — Supporting
Modification Type: Disease-specific,Gene-specific,Strength
Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
1 - 1.5 points
 will arrive at 
Supporting
. 




Complex Neurodevelopmental Disorder: 1 points


Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: PM1 — Moderate
Modification Type: Gene-specific
Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table".
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: PM2 — Supporting
Modification Type: Other
One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: PM4 — Moderate
Modification Type: No change
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: PM5 — Strong
Modification Type: Disease-specific,Gene-specific,Strength
Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).


Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Gene: SCN2A (HGNC:10588)
Evidence Code: PM5 — Moderate
Modification Type: Disease-specific,Gene-specific
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: SCN2A (HGNC:10588)
Evidence Code: PM5 — Supporting
Modification Type: Disease-specific,Gene-specific,Strength
Novel missense change at an amino acid residue where a different missense change determined to be 
Likely Pathogenic
 has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. 


>1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be 
Pathogenic
or 
Likely Pathogenic
, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)




Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Gene: SCN2A (HGNC:10588)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: SCN2A (HGNC:10588)
Evidence Code: PM6 — Strong
Modification Type: Disease-specific,Gene-specific,Strength
Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
2 points
 will arrive at 
Strong
. Total of 
4 points
 will arrive at 
Very Strong
. 




Complex Neurodevelopmental Disorder: 0.5 points


Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
Gene: SCN2A (HGNC:10588)
Evidence Code: PM6 — Moderate
Modification Type: Disease-specific,Gene-specific,Strength
Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
1 point
 will arrive at 
Moderate
. 




Complex Neurodevelopmental Disorder: 0.5 points


Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
Gene: SCN2A (HGNC:10588)
Evidence Code: PM6 — Supporting
Modification Type: Disease-specific,Gene-specific,Strength
Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
0.5 points
 will arrive at 
Supporting
. 




Complex Neurodevelopmental Disorder: 0.5 points


Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: PP1 — Strong
Modification Type: Strength
>=7 independent meioses
Gene: SCN2A (HGNC:10588)
Evidence Code: PP1 — Moderate
Modification Type: Strength
5-6 independent meioses
Gene: SCN2A (HGNC:10588)
Evidence Code: PP1 — Supporting
Modification Type: Strength
3-4 independent meioses
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: PP3 — Moderate
Modification Type: General recommendation,Strength
Follow ClinGen’s recommendations (
PMID: 36413997
), using REVEL as the computational tool, with the following stipulations:




Strength should be capped at Moderate, and 


limit the combination of PP3 and PM1 to reach no higher than strong
Gene: SCN2A (HGNC:10588)
Evidence Code: PP3 — Supporting
Modification Type: General recommendation,Strength
Follow ClinGen’s recommendations (
PMID: 36413997
), using REVEL as the computational tool, with the following stipulations:




Strength should be capped at Moderate, and 


limit the combination of PP3 and PM1 to reach no higher than strong
Gene: SCN2A (HGNC:10588)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: SCN2A (HGNC:10588)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Allele frequency is above 
0.01%
 is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.
Gene: SCN2A (HGNC:10588)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: SCN2A (HGNC:10588)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific,Gene-specific
Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: BS2 — Strong
Modification Type: No change
Observed in a healthy adult individual with full penetrance expected at an early age.
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: SCN2A (HGNC:10588)
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: SCN2A (HGNC:10588)
Evidence Code: BP2 — Supporting
Modification Type: No change
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: SCN2A (HGNC:10588)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.