Classification rationale

PM2 BP7 VUS

CDKN2A c.183G>A

The CDKN2A c.183G>A (p.Glu61=) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and observed at 0/1,596,036 alleles in gnomAD v4.1 (AF 0.00000%), which is below the 0.1% PM2 rarity threshold.² In silico data support a silent variant without splice effect: the protein consequence is p.(Glu61=), SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and REVEL is 0.083.³

PM2 + BP7 → VUS

1 cosmic ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗prefetch

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000077.5 · variants mapped to exon structure

CDKN2A NM_000077.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 17 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 Moderate review Pathogenic

This variant is absent from gnomAD v2.1 and observed at 0/1,596,036 alleles in gnomAD v4.1 (AF 0.00000%), which is below the 0.1% rarity threshold and supports rarity in population databases.

gnomAD v2.1: absentgnomAD v4.1: 0/1596036 alleles, AF 0.0, homozygotes 0

gnomad_v2 ↗gnomad_v4 ↗

BP7 Supporting review Benign

This variant is a synonymous substitution, p.(Glu61=), with no predicted effect on the protein sequence, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. These findings support a silent change without evidence of splice disruption.

Protein consequence is p.(Glu61=)SpliceAI DS_AG 0.0, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0; max delta score 0.00

spliceai ↗

Assessed · not applied · 3 not met · 14 not assessed

Pathogenic

PS2 No confirmed de novo data with verified maternity and paternity were identified for this variant.

PS3 No well-established functional studies showing a damaging effect on CDKN2A function or splicing were identified for this variant.

PS4 No evidence was identified showing this variant is enriched in affected individuals compared with controls.

PM1 Available evidence does not support location in a mutational hotspot or other well-established critical functional domain without benign variation.

PM3 No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder.

PM6 No assumed de novo occurrence data were identified for this variant.

PP1 No segregation data were identified to show that this variant tracks with disease in affected family members.

PP4 No phenotype or family-history information was provided to determine whether the clinical presentation is highly specific for a CDKN2A-related disorder.

PP5 No reputable source classification supporting pathogenicity was identified for this variant.

Benign

BA1 Population frequency does not meet the standalone benign threshold.

BS1 Population frequency does not exceed the strong benign threshold.

BS2 No evidence was identified showing this variant in healthy adults at a frequency inconsistent with disease penetrance.

BS3 No well-established functional studies demonstrating no damaging effect were identified for this variant.

BS4 No family data were identified to show lack of segregation with disease.

BP2 No phase data were identified to show this variant occurs in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.

BP5 No evidence was identified that the reported phenotype is explained by an alternate molecular cause independent of this variant.

BP6 No reputable source classification supporting a benign interpretation was identified for this variant.

N/A · 9 PVS1 · PS1 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1596036 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74908 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / 1,596,036
0 hom

Not observed in any ancestry group.

+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

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

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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