owencqueen/cgbench_data huggingface dataset:
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: PVS1 — Very Strong
Modification Type: Gene-specific
Use decision tree as per SVI WG with specified “regions critical to protein function”.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PVS1 — Strong
Modification Type: Gene-specific
Use decision tree as per SVI WG with specified “regions critical to protein function”.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PVS1 — Moderate
Modification Type: Gene-specific
Use decision tree as per SVI WG with specified “regions critical to protein function”.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PVS1 — Supporting
Modification Type: Gene-specific
Use decision tree as per SVI WG with specified “regions critical to protein function”.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: PS1 — Strong
Modification Type: Gene-specific
Use with no specification except comparison variant must be classified as pathogenic using 
SERPINC1
 rule specifications from the Thrombosis VCEP.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PS1 — Moderate
Modification Type: Gene-specific
Use with no specification except comparison variant must be classified as likely pathogenic using 
SERPINC1
 rule specifications from the Thrombosis VCEP.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: PS2 — Very Strong
Modification Type: Disease-specific
Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 4 points.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PS2 — Strong
Modification Type: Disease-specific
Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 2 points.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PS2 — Moderate
Modification Type: Disease-specific
Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 1 point.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PS2 — Supporting
Modification Type: Disease-specific
Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 0.5 point.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: PS3 — Supporting
Modification Type: Disease-specific
See attached spreadsheet for list of approved assays to use for this rule code. Below is a general description of assays that can be used:


 - 
In vitro
 functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal activity levels:




Antithrombin activity levels measured by FXa inhibition activity assay


Antithrombin activity levels measured by thrombin inhibition activity assay




OR


- 
In vitro
 functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal antigen levels:




Antithrombin antigen levels measured by ELISA


Immunofluorescence assay – intracellular retention and secretion defects








OR


- 
In vivo
 studies demonstrating rescue of antithrombin levels would be considered, but no studies are       known to be available at this time.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: PS4 — Very Strong
Modification Type: Disease-specific
Appropriate to use code when there 8 or more proband points that meet the defined antithrombin deficiency laboratory phenotype.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PS4 — Strong
Modification Type: Disease-specific
Appropriate to use code when there 4-7 proband points that meet the defined antithrombin deficiency laboratory phenotype.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PS4 — Moderate
Modification Type: Disease-specific
Appropriate to use code when there 2-3 proband points that meet the defined antithrombin deficiency laboratory phenotype.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PS4 — Supporting
Modification Type: Disease-specific
Appropriate to use code when there is 1 proband point that meets the defined antithrombin deficiency laboratory phenotype.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: PM1 — Moderate
Modification Type: Gene-specific
This code is applicable for variants disrupting cystine residues involved in disulfide bridges (Cys40, Cys53, Cys127, Cys160, Cys279, Cys462)
1
, variants that would impact heparin binding site residues (Ile39, Arg56, Pro73, Arg79) and variants involving reactive site residues (Ala414 and Ala416)
2
.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: PM2 — Supporting
Modification Type: Disease-specific,Gene-specific
Use code for variants with a popmax MAF of <0.00002 in gnomAD.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: PM4 — Moderate
Modification Type: None
No specification
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: PM5 — Moderate
Modification Type: General recommendation
Use code when previously reported variant reaches a pathogenic classification using the 
SERPINC1
 rule specifications from the Thrombosis VCEP.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PM5 — Supporting
Modification Type: General recommendation
Use code when previously reported variant reaches a likely pathogenic classification using the 
SERPINC1
 rule specifications from the Thrombosis VCEP.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: PP1 — Strong
Modification Type: Disease-specific
Appropriate to use there are 7 or more meioses across more than one family.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PP1 — Moderate
Modification Type: Disease-specific
Appropriate to use there are 4-6 meioses across one or more families.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PP1 — Supporting
Modification Type: Disease-specific
Appropriate to use when there are 2-3 meioses across one or more families.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: PP3 — Supporting
Modification Type: Gene-specific
Appropriate to use for missense variants that have a REVEL score of greater or equal to 0.6. For potential splicing variants, use of 2 independent 
in silico
 splicing tools must predict a damaging impact.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: SERPINC1 (HGNC:775)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific
Proband must have an antithrombin activity level of < 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range). confirmed on repeated independent samples. An abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function may be used in lieu of low activity levels, which is typically caused by type II variants.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: SERPINC1 (HGNC:775)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific,Gene-specific
Appropriate to use for variants with a popmax MAF of greater than or equal to 0.002 in gnomAD.
Gene: SERPINC1 (HGNC:775)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: SERPINC1 (HGNC:775)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific,Gene-specific
Appropriate to use for variants with a Popmax MAF of >0.0002 in gnomAD.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: BS2 — Strong
Modification Type: Disease-specific
This evidence code is available when the variant is identified in 2 or more heterozygotes or 1 or more homozygotes with normal antithrombin levels [> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)].
Gene: SERPINC1 (HGNC:775)
Evidence Code: BS2 — Supporting
Modification Type: Disease-specific
This evidence code is available when the variant is identified in 1 heterozygote with normal antithrombin levels [> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)].
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: BS4 — Strong
Modification Type: Disease-specific
Appropriate to use when the variant is found not to segregate in a minimum of four relatives with abnormal antithrombin activity levels [< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)] within the same family, 
OR
 the variant does not segregate in 2 or more families. Non-segregation defined by having abnormal antithrombin activity levels without 
SERPINC1
 variant of interest.
Gene: SERPINC1 (HGNC:775)
Evidence Code: BS4 — Supporting
Modification Type: Disease-specific
Appropriate to use when the variant is found not to segregate in a minimum of two relatives with abnormal antithrombin activity levels [< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)] within the same family.
Gene: SERPINC1 (HGNC:775)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: BP2 — Supporting
Modification Type: Disease-specific
This rule can be applied when a 
SERPINC1
 variant is 
in cis
 with another pathogenic 
SERPINC1
 variant. The pathogenic variant must be evaluated using ClinGen 
SERPINC1
 specified rules. This rule cannot be applied to a variant 
in trans
 with a pathogenic variant, as this scenario could reasonably occur and increase the risk of venous thrombosis.
Gene: SERPINC1 (HGNC:775)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: BP4 — Supporting
Modification Type: Gene-specific
Use this code for missense variants with a REVEL score of < 0.30 and no evidence of a potential splicing effect using VarSEAK and Splice AI prediction tools, or for non-canonical intronic variants with no evidence of a potential splicing effect using VarSEAK and Splice AI prediction tools.
Gene: SERPINC1 (HGNC:775)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
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: SERPINC1 (HGNC:775)
Evidence Code: BP7 — Supporting
Modification Type: General recommendation
Use tools VarSEAK and Splice AI to rule out a predicted splicing effect. Evolutionary conservation is defined as a PhyloP < 0.1 
OR
 the reference nucleotide is present in 3 mammals or 1 primate.