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).1 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).2 ClinVar records show two submissions of Uncertain significance and one submission of Likely benign; no pathogenic classification has been reported.3 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.4 The net evidence profile (1 supporting pathogenic criterion, 2 supporting benign criteria) is consistent with a variant of uncertain significance.
CDKN2A
Final classification
Likely Benign
CDKN2A c.306G>T · p.Ala102=
CDKN2A
NM_000077.5:c.306G>T is a synonymous variant (p.Ala102=) in exon 2 of CDKN2A.
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.
Classification rationale
PM2
BP4BP7
Likely Benign
CDKN2A c.306G>T
PM2 + BP4 + BP7
→
Likely Benign
Gene diagram
· NM_000077.5 · variants mapped to exon structure
CDKN2A
NM_000077.5
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
gnomAD v2.1: absent.gnomAD v4.1: absent.gnomAD-Canada v1.0: absent.
✓
BP4
supporting
Benign
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.
REVEL: 0.182 (benign).BayesDel: -0.230 (benign).SpliceAI: 0.00 (no splicing impact).
✓
BP7
supporting
Benign
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.
Synonymous variant: p.Ala102=.SpliceAI: max delta = 0.00 (no predicted splicing impact).REVEL: 0.182 (low conservation).
Assessed · not applied
Pathogenic
PS2
No de novo data are available for this variant.
PS3
No functional studies assessing the biological effect of NM_000077.5:c.306G>T have been identified in the literature.
PS4
No case-control studies or multiple unrelated proband observations are available for this variant.
PM1
c.306G>T is a synonymous variant at codon 102 of CDKN2A.
PM6
No de novo observations have been reported for this variant.
PP1
No segregation data are available for this variant.
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).
PP4
No patient phenotype data are available for this variant.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
NM_000077.5:c.306G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
NM_000077.5:c.306G>T is absent from population databases.
BS2
No homozygous observations or observations in trans with a known pathogenic CDKN2A variant have been reported.
BS3
No functional studies demonstrating a benign effect have been identified.
BS4
No segregation data are available to demonstrate lack of cosegregation with disease.
BP2
No phase data are available.
BP5
No alternate molecular basis for disease has been identified in an individual carrying this variant.
BP6
ClinVar submissions for NM_000077.5:c.306G>T include two Uncertain significance classifications (GeneDx, Invitae) and one Likely benign classification (Ambry Genetics).
N/A · 5
PVS1 · PS1 · PM5 · PP2 · BP1
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.
Sources & reference links
Triaged references · 4 PMIDs not cited in assessment
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
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR