Classification rationale

PM2 BP4 VUS

H3C2 c.290G>C

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).¹ BP4_Supporting is met: multiple in silico tools predict a benign effect — REVEL 0.117, BayesDel −0.262, SpliceAI max delta 0.05.² 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).³

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

3 generic_acmg_combination_rules

Gene diagram · NM_003537.3 · variants mapped to exon structure

H3C2 NM_003537.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 19 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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 v2.1: 0/251472 alleles (AF=0.0).gnomAD v4.1: 2/1

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

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: 0.117 (well below 0.29–0.5 pathogenic range).BayesDel: −0.262 (negative score indicates benign).SpliceAI: max delta 0.05 (no splicing alteration predicted).

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No prior pathogenic classification of this specific variant exists at this amino acid position from a reputable source.

PS2 No de novo data available for this variant.

PS3 No well-established in vitro or in vivo functional studies identified for this specific variant.

PS4 Variant absent from ClinVar.

PM1 Not located in a statistically significant mutational hotspot.

PM6 No de novo reports identified for this variant.

PP1 No segregation data available for this variant.

PP2 H3C2 lacks established ClinGen gene-disease validity with missense as a common pathogenic mechanism.

PP3 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).

PP4 No specific phenotype or family history data available for this variant.

PP5 Variant absent from ClinVar.

Benign

BA1 Allele frequency of 1.24×10⁻⁶ in gnomAD v4.1 is far below the 1% BA1 threshold.

BS1 Allele frequency of 1.24×10⁻⁶ in gnomAD v4.1 is far below the 0.3% BS1 threshold.

BS2 Two heterozygous observations in gnomAD v4.1 (0 homozygotes) without established fully penetrant disease mechanism for H3C2.

BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this variant.

BS4 No segregation data showing lack of cosegregation with disease.

BP2 No observation of this variant in trans with a known pathogenic variant.

BP5 No case with an alternate molecular basis for disease identified.

BP6 No reputable source classifies this variant as benign.

N/A · 7 PVS1 · PM3 · PM4 · PM5 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.23896e-06; MAF= 0.00012%, 2/1614256 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69485e-06; MAF= 0.00017%, 2/1180044 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251472 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,614,256
0 hom · FAF 2.8e-05%

European (non-Finnish)

2 / 1,180,044

0.00017%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / 251,472
0 hom

Not observed in any ancestry group.

+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.117. BayesDel score = -0.262425.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. H3C2, a histone variant, is recurrently altered by mutation in various pediatric cancers, including pediatric glioblastoma.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Re-run this variant?