CDKN2Ac.306G>TLikely benign

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Variant interpretation report

CDKN2A c.306G>T, p.(Ala102=)

NM_000077.5:c.306G>T NP_000068.1:p.(Ala102=) View identifiers

Classification

Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About CDKN2A

No gene-level summary was recorded for this case.

Key facts

Evidence used: 2 supporting (benign) · 1 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 2 Uncertain significance · 1 Likely benign
Pipeline record: 9 Jul 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): NM_000077.5:c.306G>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold for allele frequency below 0.1% in population databases.
BP4 (supporting): Multiple lines of computational evidence suggest no deleterious impact: REVEL score 0.182 (below 0.5 pathogenic threshold), BayesDel score -0.230 (negative = benign), and SpliceAI max delta score 0.00 (no predicted splicing alteration). These concordant in silico predictions support a benign interpretation.
BP7 (supporting): NM_000077.5:c.306G>T is a synonymous variant (p.Ala102=) with no predicted splicing impact. SpliceAI max delta score is 0.00, indicating no effect on splice consensus sequences or creation of a new splice site. In silico predictors (REVEL 0.182, BayesDel -0.230) suggest the nucleotide position is not highly conserved.

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.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 2

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

NM_000077.5:c.306G>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold for allele frequency below 0.1% in population databases.

Benign criteria applied · 2

BP4Supporting

BP4 · supporting

Multiple lines of computational evidence suggest no deleterious impact: REVEL score 0.182 (below 0.5 pathogenic threshold), BayesDel score -0.230 (negative = benign), and SpliceAI max delta score 0.00 (no predicted splicing alteration). These concordant in silico predictions support a benign interpretation.

BP7Supporting

BP7 · supporting

NM_000077.5:c.306G>T is a synonymous variant (p.Ala102=) with no predicted splicing impact. SpliceAI max delta score is 0.00, indicating no effect on splice consensus sequences or creation of a new splice site. In silico predictors (REVEL 0.182, BayesDel -0.230) suggest the nucleotide position is not highly conserved.

Recorded classification: Likely benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting, BP7 supporting; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗

ClinVar submissions

3 reported laboratory submissions

2 Uncertain significance · 1 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 3 met · 18 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000077.5:c.306G>T is a synonymous variant (p.Ala102=) in exon 2 of CDKN2A.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).

SpliceAI predicts no splicing impact (max delta score 0.00), and in silico tools REVEL (0.182) and BayesDel (-0.230) support a benign interpretation (BP4_Supporting, BP7_Supporting).

ClinVar records show two submissions of Uncertain significance and one submission of Likely benign; no pathogenic classification has been reported.

No functional studies, case reports, segregation data, or de novo observations are available for this variant. All four PMIDs reviewed (25394175, 26389258, 26389333, 28492532) are general guidance or methodology papers that do not mention the specific variant.

The net evidence profile (1 supporting pathogenic criterion, 2 supporting benign criteria) is consistent with a variant of uncertain significance.

Met · 3

PM2 SupportingNM_000077.5:c.306G>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold for allele frequency below 0.1% in population databases. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent.
gnomAD v4.1: absent.
gnomAD-Canada v1.0: absent.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact: REVEL score 0.182 (below 0.5 pathogenic threshold), BayesDel score -0.230 (negative = benign), and SpliceAI max delta score 0.00 (no predicted splicing alteration). These concordant in silico predictions support a benign interpretation. Details ▾Hide ▴

Evidence considered

REVEL: 0.182 (benign).
BayesDel: -0.230 (benign).
SpliceAI: 0.00 (no splicing impact).

Sources

revelbayesdelspliceai ↗

BP7 SupportingNM_000077.5:c.306G>T is a synonymous variant (p.Ala102=) with no predicted splicing impact. SpliceAI max delta score is 0.00, indicating no effect on splice consensus sequences or creation of a new splice site. In silico predictors (REVEL 0.182, BayesDel -0.230) suggest the nucleotide position is not highly conserved. Details ▾Hide ▴

Evidence considered

Synonymous variant: p.Ala102=.
SpliceAI: max delta = 0.00 (no predicted splicing impact).
REVEL: 0.182 (low conservation).
BayesDel: -0.230 (benign).

Sources

spliceai ↗revelbayesdel

Not met · 18 · evaluated, threshold not reached

PS2 No de novo data are available for this variant. No publications report de novo occurrence of NM_000077.5:c.306G>T. Details ▾Hide ▴

Evidence considered

No de novo observations reported in any available source.

Still missing

No parent-of-origin testing data available.

PS3 No functional studies assessing the biological effect of NM_000077.5:c.306G>T have been identified in the literature. OncoKB lists this variant as having unknown oncogenic effect with no curated functional data. Details ▾Hide ▴

Evidence considered

No variant-specific functional studies available.
OncoKB: Unknown Oncogenic Effect.

Still missing

No functional assay data (e.g.
splicing assay
minigene
protein function).

Sources

oncokb ↗

PS4 No case-control studies or multiple unrelated proband observations are available for this variant. No publications report affected individuals carrying NM_000077.5:c.306G>T. Details ▾Hide ▴

Evidence considered

No proband counts or case-control data available.

Still missing

No clinical phenotype data or cohort studies.

PM1 c.306G>T is a synonymous variant at codon 102 of CDKN2A. This position has not been identified as a mutational hotspot in cancerhotspots.org, nor does it fall within a recognized functional domain with enrichment of pathogenic variants and absence of benign variation. OncoKB shows unknown oncogenic effect. Details ▾Hide ▴

Evidence considered

Cancer Hotspots: no significant hotspot at this residue.
OncoKB: Unknown Oncogenic Effect.

Sources

oncokb ↗

PM6 No de novo observations have been reported for this variant. No publications document a de novo occurrence of NM_000077.5:c.306G>T with confirmed maternity and paternity. Details ▾Hide ▴

Evidence considered

No de novo data available.

Still missing

No parentage-confirmed de novo reports.

PP1 No segregation data are available for this variant. No family studies have been published. Details ▾Hide ▴

Evidence considered

No cosegregation data available.

Still missing

No family-based segregation studies.

PP3 Multiple in silico tools predict a benign effect: REVEL score 0.182 (below pathogenic threshold), BayesDel score -0.230 (negative = benign), and SpliceAI max delta 0.00 (no predicted splicing impact). These data do not support a pathogenic interpretation. Details ▾Hide ▴

Evidence considered

REVEL: 0.182 (benign range).
BayesDel: -0.230 (benign score).
SpliceAI: max delta = 0.00 (no splicing impact).

Sources

revelbayesdelspliceai ↗

PP4 No patient phenotype data are available for this variant. No case reports or clinical series describe individuals carrying NM_000077.5:c.306G>T with a phenotype specific for CDKN2A-associated disease. Details ▾Hide ▴

Evidence considered

No clinical phenotype data available.

Still missing

No patient phenotypes reported in the literature or ClinVar.

PP5 No reputable source has classified this variant as pathogenic. ClinVar records show two submissions as Uncertain significance (GeneDx, Invitae) and one as Likely benign (Ambry Genetics). None classify as pathogenic. Details ▾Hide ▴

Evidence considered

ClinVar: 2 VUS + 1 Likely benign
no pathogenic classification.

Sources

clinvar ↗

BA1 NM_000077.5:c.306G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the BA1 threshold of >1%. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF = 0%.
gnomAD v4.1: AF = 0%.
gnomAD-Canada: AF = 0%.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 NM_000077.5:c.306G>T is absent from population databases. The allele frequency is 0%, well below the BS1 threshold of >0.3%. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF = 0%.
gnomAD v4.1: AF = 0%.
gnomAD-Canada: AF = 0%.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS2 No homozygous observations or observations in trans with a known pathogenic CDKN2A variant have been reported. Insufficient data to support BS2. Details ▾Hide ▴

Evidence considered

No homozygous or compound heterozygous observations available.

Still missing

No phase data or homozygous observations.

BS3 No functional studies demonstrating a benign effect have been identified. No variant-specific functional assays (e.g., splicing minigene, protein function) have been published for NM_000077.5:c.306G>T. Details ▾Hide ▴

Evidence considered

No benign functional evidence available.

Still missing

No splicing or protein-level functional studies.

BS4 No segregation data are available to demonstrate lack of cosegregation with disease. No family studies have been published for this variant. Details ▾Hide ▴

Evidence considered

No cosegregation data available.

Still missing

No family segregation studies.

BP2 No phase data are available. No observations of this variant in trans with a pathogenic CDKN2A variant, nor in cis with a pathogenic variant, have been reported. Details ▾Hide ▴

Evidence considered

No phase data available.

Still missing

No in trans or in cis observations.

BP5 No alternate molecular basis for disease has been identified in an individual carrying this variant. No data are available to suggest this variant is incidental to an alternative genetic diagnosis. Details ▾Hide ▴

Evidence considered

No alternate molecular diagnosis data available.

Still missing

No data on alternate causative variants in carriers.

BP6 ClinVar submissions for NM_000077.5:c.306G>T include two Uncertain significance classifications (GeneDx, Invitae) and one Likely benign classification (Ambry Genetics). The majority classification is VUS; no consensus benign classification from a reputable source has been established. Details ▾Hide ▴

Evidence considered

ClinVar: 2 VUS
1 Likely benign.
Ambry Genetics Likely benign is a single-submitter classification
not a consensus.

Sources

clinvar ↗

PS5 No reputable source has classified this variant as pathogenic. ClinVar submissions include two VUS classifications (GeneDx, Invitae) and one Likely benign (Ambry Genetics); none classify as pathogenic. Details ▾Hide ▴

Evidence considered

ClinVar: 2 VUS
1 Likely benign
no pathogenic classification.

Sources

clinvar ↗

Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ANM_000077.5:c.306G>T is a synonymous variant (p.Ala102=) that does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants (PMC6185798). Details ▾Hide ▴

Evidence considered

Synonymous variant with no predicted protein truncation or splice disruption.

Sources

pvs1_variant_assessmentpvs1_generic_framework ↗

PS1 N/APS1 requires a different nucleotide change producing the same missense amino acid change as a known pathogenic variant. This is a synonymous variant; no alternate nucleotide change at the same codon could produce a different missense change. Details ▾Hide ▴

Evidence considered

Synonymous variant — no pathogenic comparator applicable.

PM5 N/APM5 requires a different missense change at the same residue that has already been established as pathogenic. c.306G>T is a synonymous variant (p.Ala102=) with no amino acid change; no pathogenic comparator at the same residue is applicable. Details ▾Hide ▴

Evidence considered

Synonymous variant — no missense comparators at codon 102.

Sources

pm5_candidates

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. c.306G>T is a synonymous variant, not a missense change. Details ▾Hide ▴

Evidence considered

Synonymous variant — PP2 is restricted to missense variants.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. c.306G>T is a synonymous variant, not a missense change. Details ▾Hide ▴

Evidence considered

Synonymous variant — BP1 is restricted to missense variants.

Identifiers

Gene: CDKN2A
Transcript: NM_000077.5
Coding (HGVS c.): NM_000077.5:c.306G>T
Protein (HGVS p.): NP_000068.1:p.(Ala102=)
GRCh38: chr9:21971053 C>A
GRCh37: chr9:21971052 C>A
ClinVar: 421033

Gene diagram

Every interpreted variant in CDKN2A, mapped onto the exon structure of NM_000077.5. Select a row to find it on the plot.

CDKN2ANM_000077.5

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in CDKN2A — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.020

Other predictors

REVEL: 0.182
BayesDel: -0.230

How the predictions were used

Evidence considered

REVEL: 0.182 (benign).
BayesDel: -0.230 (benign).
SpliceAI: 0.00 (no splicing impact).

Sources

revelbayesdelspliceai ↗

Evidence considered

Synonymous variant: p.Ala102=.
SpliceAI: max delta = 0.00 (no predicted splicing impact).
REVEL: 0.182 (low conservation).
BayesDel: -0.230 (benign).

Sources

spliceai ↗revelbayesdel

Evidence considered

REVEL: 0.182 (benign range).
BayesDel: -0.230 (benign score).
SpliceAI: max delta = 0.00 (no splicing impact).

Sources

revelbayesdelspliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.182. BayesDel score = -0.230355.

4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

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.

Hampel H et al. · 2015

Practice guideline from ACMG and NSGC providing referral indications for cancer predisposition assessment. Discusses CDKN2A-associated familial atypical mole and malignant melanoma syndrome at the gene level. NM_000077.5:c.306G>T was not identified in this paper.
Does not name this variant
PMID 25394175 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.

PDQ Cancer Genetics Editorial Board · 2002

PDQ cancer genetics risk assessment and counseling summary covering hereditary cancer syndromes at the gene level. NM_000077.5:c.306G>T was not identified in this paper.
Does not name this variant
PMID 26389258 ↗
Genetics of Skin Cancer (PDQ®): Health Professional Version.

PDQ Cancer Genetics Editorial Board · 2002

PDQ genetics of skin cancer summary covering melanoma predisposition genes including CDKN2A at the gene level. NM_000077.5:c.306G>T was not identified in this paper.
Does not name this variant
PMID 26389333 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K et al. · 2017

Sherloc classification methodology paper describing refinement of ACMG-AMP criteria. NM_000077.5:c.306G>T was not identified in this paper.
Does not name this variant
PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 2 Uncertain significance · 1 Likely benign Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 421033)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.182. BayesDel score = -0.230355.

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.