owencqueen/cgbench_data huggingface dataset:
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: PVS1 — Very Strong
Modification Type: Gene-specific
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:




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 the PVS1 decision tree guide.
Gene: BMPR2 (HGNC:1078)
Evidence Code: PVS1 — Strong
Modification Type: Gene-specific,Strength
Use the PVS1 decision tree guide.
Gene: BMPR2 (HGNC:1078)
Evidence Code: PVS1 — Moderate
Modification Type: Gene-specific,Strength
Use the PVS1 decision tree guide.
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: PS1 — Strong
Modification Type: None
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: BMPR2 (HGNC:1078)
Evidence Code: PS1 — Moderate
Modification Type: Strength
Same amino acid change as a previously established 
likely pathogenic
 variant regardless of nucleotide change.
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: PS2 — Strong
Modification Type: No change
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: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: PS3 — Strong
Modification Type: General recommendation,Gene-specific
Use the BMPR2 functional assay document for guidance on allowable assays. Known variant validation controls (i.e. established pathogenic and benign variants) are required. One exception is if the same functional assay has been performed for the same variant by two independent groups and demonstrated to have the same functional effect by both groups. Also applicable for non-canonical splice site variants when RNA splice site assay data is available demonstrating abnormal splicing; positive and negative controls are required, preferably from patients and matched unaffected individuals. Note that splicing assay results may be tissue-sensitive.
Gene: BMPR2 (HGNC:1078)
Evidence Code: PS3 — Supporting
Modification Type: General recommendation
Use the BMPR2 functional assay document for guidance on allowable assays. If no known variant validation controls (i.e. established pathogenic and benign variants) were used, then score at the supporting strength.
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: PS4 — Strong
Modification Type: Disease-specific
Prior observation of the variant in >4 unrelated patients with the same phenotype, and its absence in controls.
Gene: BMPR2 (HGNC:1078)
Evidence Code: PS4 — Moderate
Modification Type: Disease-specific,Strength
Prior observation of the variant in >3 unrelated patients with the same phenotype, and its absence in controls.
Gene: BMPR2 (HGNC:1078)
Evidence Code: PS4 — Supporting
Modification Type: Disease-specific,Strength
Prior observation of the variant in >1 unrelated patients with the same phenotype, and its absence in controls.
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: PM1 — Strong
Modification Type: Gene-specific,Strength
Variant changes a 
critical
 amino acid. Extracellular domain: p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123. Kinase domain: p.Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Arg491. KD heterodimerization: p.Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Leu492.


Note that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated 
non-critical/not necessary
 for kinase activity based on a luciferase assay (apply BS3).
Gene: BMPR2 (HGNC:1078)
Evidence Code: PM1 — Moderate
Modification Type: Gene-specific
Variant changes an amino acid in the extracellular domain (aa 33-131) or kinase domain (aa 203-504) but without functional evidence indicating critical or non-critical.


Note that p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123, Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Arg491, and Leu492 have been demonstrated 
critical
 (apply PM1_strong).


Note that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated 
non-critical/not necessary
 for kinase activity based on a luciferase assay (apply BS3).
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: PM2 — Supporting
Modification Type: Disease-specific
Present at <0.01% among gnomAD controls, using the subpopulation with the highest frequency and at least 1,000 allele counts. Caveat: Population data for indels may be poorly called by next generation sequencing.
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: PM5 — Moderate
Modification Type: General recommendation
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.  Also applicable for variants affecting the same splice site as a confirmed splice variant with similar or worse splicing in silico predictions
Gene: BMPR2 (HGNC:1078)
Evidence Code: PM5 — Supporting
Modification Type: Strength
Novel missense change at an amino acid residue where a different missense change determined to be 
likely pathogenic
 has been seen before.
Gene: BMPR2 (HGNC:1078)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: BMPR2 (HGNC:1078)
Evidence Code: PM6 — Moderate
Modification Type: No change
Assumed de novo, but without confirmation of paternity and maternity.
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: PP1 — Strong
Modification Type: Strength
Co-segregation with disease in ≥7 affected family members.
Gene: BMPR2 (HGNC:1078)
Evidence Code: PP1 — Moderate
Modification Type: Strength
Co-segregation with disease in ≥5 affected family members.
Gene: BMPR2 (HGNC:1078)
Evidence Code: PP1 — Supporting
Modification Type: Strength
Co-segregation with disease in ≥3 affected family members.
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: PP3 — Supporting
Modification Type: General recommendation
REVEL ≥0.75 for missense variants or Splice AI ≥0.2 for non-canonical splice variants. No up/downgrading. If no REVEL score or SpliceAI prediction is available, then CADD ≥20 can be used. Note: can be applied additively with PS3 if applicable.
Gene: BMPR2 (HGNC:1078)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: BMPR2 (HGNC:1078)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Allele frequency is above 1% in gnomAD, including any sub-population with at least 1,000 allele counts.
Gene: BMPR2 (HGNC:1078)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: BMPR2 (HGNC:1078)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Allele frequency >=0.1% among gnomAD controls, using the subpopulation with the highest frequency and at least 1,000 allele counts.
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: BS2 — Strong
Modification Type: Disease-specific,Gene-specific
Observed in ≥3 homozygotes in gnomAD controls or reported in the literature (healthy adult individuals).
Gene: BMPR2 (HGNC:1078)
Evidence Code: BS2 — Supporting
Modification Type: Disease-specific,Gene-specific
Observed in ≥2 homozygotes in gnomAD controls or reported in the literature (healthy adult individuals).
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: BS3 — Strong
Modification Type: Gene-specific
Use the BMPR2 functional assay document for acceptable assays and guidance. Note that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated non-critical/not necessary for kinase activity based on a luciferase assay (apply BS3).


Note that p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123, Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Arg491, and Leu492 have been demonstrated 
critical
 (apply PM1_strong).
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: BS4 — Strong
Modification Type: No change
Lack of variant segregation in affected members of a family.
Gene: BMPR2 (HGNC:1078)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: BMPR2 (HGNC:1078)
Evidence Code: BP3 — Supporting
Modification Type: No change
In frame-deletions/insertions in a repetitive region without a known function.
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: BP4 — Supporting
Modification Type: General recommendation
REVEL ≤0.25 for missense variants or Splice AI ≤0.1 for non-canonical splice variants. No up/downgrading. If no REVEL or. Splice AI available, then CADD ≤ 10 can be used.
Gene: BMPR2 (HGNC:1078)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
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: BMPR2 (HGNC:1078)
Evidence Code: BP7 — Strong
Modification Type: Strength
If BP7 is met and negative RNA splicing assay data is available, then apply BP7_strong. Acceptable splicing assays should have positive and negative controls, preferably from patients and matched unaffected individuals. Note that splicing assay results may be tissue-sensitive.
Gene: BMPR2 (HGNC:1078)
Evidence Code: BP7 — Supporting
Modification Type: No change
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. Applicable after assignment of BP4 for no adverse splicing predictions, and inclusive of exonic and intronic variants. Not applicable for synonymous variants located at the first base or the last three bases of an exon.