Classification rationale

PM2 BP4 VUS

CDKN2A c.76G>C missense · exon 1

PM2 (Supporting): extremely rare in population databases, with gnomAD v4.1 allele frequency 0.000124% (2/1,611,012 alleles). BP4 (Supporting): SpliceAI max delta 0.006 and REVEL 0.155, both below calibrated benign-supporting thresholds. Overall classification: VUS — PM2 (Supporting) plus BP4 (Supporting) does not reach any ACMG/AMP 2015 combination threshold.

PM2 + BP4 → VUS

Gene diagram · NM_000077.4 · variants mapped to exon structure

CDKN2A NM_000077.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (Supporting): extremely rare in population databases, with gnomAD v4.1 allele frequency 0.000124% (2/1,611,012 alleles).

gnomAD v4.1: total AC/AN 2/1,611,012 (AF 0.000124%), South Asian AC/AN 2/91,020 (AF 0.00220%), zero homozygotes, and grpmax FAF 0.000365%.gnomAD v2.1: total AC/AN 2/238,850 (AF 0.00084%), South Asian AC/AN 2/30,456 (AF 0.00657%), zero homozygotes, and grpmax FAF 0.001087%.gnomAD-Canada v1.0 reported the variant absent.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (Supporting): SpliceAI max delta 0.006 and REVEL 0.155, both below calibrated benign-supporting thresholds.

SpliceAI Lookup for NM_000077.4:c.76G>C reports max delta score = 0.006 (DS_AG=0.001, DS_AL=0.0, DS_DG=0.006, DS_DL=0.0), indicating no predicted disruption of splicing, consistent with a benign in silico prediction.Local REVEL v1.3 lookup for this variant returns a score of 0.155, below calibrated REVEL benign-supporting thresholds (ClinGen SVI REVEL calibration, PMID 36413997), consistent with a benign missense in silico prediction.

spliceai ↗

Assessed · not applied · 6 not met · 15 not assessed

Pathogenic

PS1 Not assessed: no other reported variant producing the same amino-acid change p.Glu26Gln was identified.

PS2 Not assessed: no de novo occurrence with parental testing was documented.

PS3 Not assessed: no validated functional assay of this variant was identified; the ClinVar submitter confirms functional studies have not been reported.

PS4 Not assessed: no case-control or enrichment data for this exact variant were available.

PM1 Not assessed: the variant is not in a statistical mutational hotspot, and no domain/structural source was available to evaluate residue 26.

PM5 Not assessed: no different pathogenic missense at the same residue (position 26) was identified.

PM6 Not assessed: no de novo occurrence with unconfirmed parentage was reported.

PP1 Not assessed: no family segregation or pedigree data were available.

PP2 Not assessed: missense is a recognized disease mechanism in CDKN2A, but no gene-level missense constraint metric was available to verify the threshold.

PP3 Not met: REVEL 0.155 and SpliceAI max delta 0.006 are far below any pathogenic-supporting threshold.

PP4 Not assessed: no proband phenotype or differential assessment was provided.

PP5 Not met: all three ClinVar submissions classify this variant as uncertain significance, with no expert-panel pathogenic assertion.

Benign

BA1 Not met: highest population frequency is 0.00657% (gnomAD v2.1 South Asian), far below a stand-alone benign threshold.

BS1 Not met: highest observed frequency 0.00657% is too low to exceed the benign expectation for this condition.

BS2 Not assessed: population records lack unaffected-carrier adult phenotype data.

BS3 Not assessed: no functional study of this variant showing normal function was identified.

BS4 Not assessed: no informative non-segregation data (affected non-carriers or unaffected carriers) were available.

BP1 Not met: CDKN2A missense variants are a recognized disease mechanism, so the truncating-only-gene premise does not apply.

BP2 Not assessed: no phase data or observation of this variant alongside a pathogenic variant in the same individual.

BP5 Not assessed: no affected individual or alternate molecular diagnosis was provided.

BP6 Not met: no expert-panel benign assertion exists; ClinVar has only uncertain-significance laboratory submissions.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.24146e-06; MAF= 0.00012%, 2/1611012 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19732e-05; MAF= 0.00220%, 2/91020 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 8.37346e-06; MAF= 0.00084%, 2/238850 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.56685e-05; MAF= 0.00657%, 2/30456 alleles, homozygotes = 0); grpmax FAF= 1.087e-05.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,611,012
0 hom · FAF 0.00037%

South Asian

2 / 91,020

0.0022%

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

gnomAD v2.1

0.00084% · 2 / 238,850
0 hom · FAF 0.0011%

South Asian

2 / 30,456

0.0066%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 919572)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.155. BayesDel score = -0.34194.

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. CDKN2A, which encodes both a cyclin-dependent kinase inhibitor and an MDM2 inhibitor, is altered by mutation and deletion in various cancers.

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

Triaged references · 4 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR

26389333 ↗ Genetics of Skin Cancer (PDQ®): Health Professional Version. CLINVAR