NM_003537.3:c.290G>C

H3C2 · NP_003528.1:p.(Cys97Ser) · NM_003537.3

GRCh37: chr6:26031999 C>G · GRCh38: chr6:26031771 C>G

Gene: H3C2 Transcript: NM_003537.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

H3C2

Transcript

NM_003537.3

Protein

NP_003528.1:p.(Cys97Ser)

gnomAD AF

1.2389608587485503e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2_Supporting is met: variant is absent from gnomAD v2.1 and near-absent in gnomAD v4.1 (2/1,614,256 alleles; AF=1.24×10⁻⁶).

BP4_Supporting is met: multiple in silico tools predict a benign effect — REVEL 0.117, BayesDel −0.262, SpliceAI max delta 0.05.

Under generic ACMG/AMP 2015 combination rules (PMID:25741868), the evidence profile of 1 supporting pathogenic (PM2) and 1 supporting benign (BP4) does not meet the threshold for Likely Pathogenic (requires at least 1 moderate + 4 supporting, or 2 moderate + 2 supporting, etc.) or Likely Benign (requires 2 supporting benign criteria). The variant is classified as Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Missense variant (p.Cys97Ser). Does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	No prior pathogenic classification of this specific variant exists at this amino acid position from a reputable source. Variant is absent from ClinVar.	clinvar
PS2	Not assessed	No de novo data available for this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies identified for this specific variant. OncoKB found no variant-specific curated functional evidence.	oncokb
PS4	Not assessed	Variant absent from ClinVar. No case-control, cohort, or clinical prevalence data available.	clinvar
PS5	Not assessed	Variant absent from ClinVar. No established pathogenic variant at the same residue to serve as a comparator for PS5.	clinvar
PM1	Not met	Not located in a statistically significant mutational hotspot. No HCI prior domain data available for H3C2.
PM2	Met	Variant is absent from gnomAD v2.1 (0/251,472 alleles) and near-absent in gnomAD v4.1 (2/1,614,256 alleles; AF=1.24×10⁻⁶), well below the 0.1% PM2 threshold. Also absent from gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No confirmed pathogenic comparator variants at the same residue (Cys97) identified. PM5 candidate harvesting returned zero candidates.	pm5_candidates
PM6	Not assessed	No de novo reports identified for this variant.
PP1	Not assessed	No segregation data available for this variant.
PP2	Not assessed	H3C2 lacks established ClinGen gene-disease validity with missense as a common pathogenic mechanism. No CSPEC/VCEP framework available for PP2 applicability assessment.
PP3	Not met	Multiple computational tools do not support a deleterious effect: REVEL 0.117 (below typical pathogenic threshold of 0.29–0.5), BayesDel −0.262 (benign direction), and SpliceAI max delta 0.05 (no predicted splice impact).	revel bayesdel spliceai
PP4	Not assessed	No specific phenotype or family history data available for this variant.
PP5	Not assessed	Variant absent from ClinVar. No expert panel classification or reputable source classification available.	clinvar
BA1	Not met	Allele frequency of 1.24×10⁻⁶ in gnomAD v4.1 is far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	Allele frequency of 1.24×10⁻⁶ in gnomAD v4.1 is far below the 0.3% BS1 threshold. Variant is absent from gnomAD v2.1.	gnomad_v2 gnomad_v4
BS2	Not assessed	Two heterozygous observations in gnomAD v4.1 (0 homozygotes) without established fully penetrant disease mechanism for H3C2. Insufficient to assess under BS2 in a generic ACMG framework.	gnomad_v4
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this variant.
BS4	Not assessed	No segregation data showing lack of cosegregation with disease.
BP1	N/A	H3C2 has no established disease mechanism limited exclusively to truncating variants. BP1 applies only when missense variants occur in genes where only truncating variants cause disease.
BP2	Not assessed	No observation of this variant in trans with a known pathogenic variant.
PM3	N/A	No phase-confirmed observation in trans with a pathogenic variant. No CSPEC/VCEP framework available for H3C2.
PM4	N/A	PM4 applies to in-frame deletions/insertions and stop-loss variants; NM_003537.3:c.290G>C is a missense substitution.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution.
BP4	Met	Multiple lines of computational evidence suggest a benign effect: REVEL score 0.117 (below all pathogenic thresholds), BayesDel score −0.262 (benign direction), and SpliceAI max delta 0.05 (no predicted splice impact).	revel bayesdel spliceai
BP5	Not assessed	No case with an alternate molecular basis for disease identified.
BP6	Not assessed	No reputable source classifies this variant as benign. Variant is absent from ClinVar.	clinvar
BP7	N/A	NM_003537.3:c.290G>C is a missense variant (p.Cys97Ser), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing effect.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.