Classification rationale

PM2 BP4 VUS

CDKN2A c.75A>G synonymous · exon 1

PM2 supporting: gnomAD v4.1 allele frequency is 6.83e-06, below the 0.0001 threshold. BP4 supporting: SpliceAI maximum delta score is 0.006, below the 0.1 threshold for synonymous variants.

PM2 + BP4 → VUS

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 · 18 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 at supporting strength: gnomAD v4.1 allele frequency is 6.83e-06, below the PM2 threshold of 0.0001, with zero homozygotes.

The case has no applicable CDKN2A-specific VCEP framework; the supplied generic PM2 threshold is AF <=0.0001 at supporting strength.gnomAD v4.1 reports total AF 6.829634155124585e-06 from 11/1,610,628 alleles, highest subpopulation AF 9.32615953837206e-06 in Europeans (non-Finnish), and zero homozygotes.The variant is absent from gnomAD v2.1 and from the available gnomAD v2.1 and v3.1 non-cancer subsets.

gnomad_v4 ↗gnomad_v2 ↗PMID:25741868 ↗

BP4 supporting Benign

Met, supporting: synonymous variant SpliceAI max delta 0.006 meets the <=0.1 BP4 threshold.

The normalized consequence is synonymous: NM_000077.5:c.75A>G, NP_000068.1:p.(Val25=).SpliceAI reports a maximum delta score of 0.006.For synonymous variants, SpliceAI is the sole applicable PP3/BP4 path; the supplied generic BP4 supporting threshold is <=0.1, from the SpliceAI calibration of Jaganathan et al. 2019 (PMID:30661751).

spliceai ↗

Assessed · not applied · 5 not met · 13 not assessed

Pathogenic

PS2 Not assessed: no documented de novo observation with confirmed parental maternity, paternity, and parental test results.

PS3 Not assessed: no validated functional assay, control data, or variant-specific experimental result was identified for synonymous c.75A>G (p.Val25=).

PS4 Not assessed: no variant-specific affected-case/control counts or enrichment statistic are available for PS4.

PM3 Not assessed: no affected-proband observation, second pathogenic allele, or documented trans phase is available for NM_000077.5:c.75A>G.

PM6 Not assessed: no presumed de novo observation or affected-proband and parental evidence is documented.

PP1 Not assessed: no affected relatives, informative meioses, or genotype-phenotype segregation data are documented.

PP3 Not met: synonymous variant SpliceAI max delta 0.006 is below the >=0.2 PP3 threshold.

PP4 Not assessed: no patient phenotype or disease-specific phenotype-match evidence is documented for this exact variant.

PP5 Not met: the exact ClinVar record has 0 expert-panel submissions and only non-expert benign assertions.

Benign

BA1 Not met: gnomAD v4.1 allele frequency is 6.83e-06, far below the generic BA1 threshold of 0.05.

BS1 Not met: gnomAD v4.1 allele frequency is 6.83e-06, below the generic BS1 threshold of 0.01.

BS2 Not assessed: gnomAD reports zero homozygotes but provides no verified healthy-adult carrier observations required for BS2.

BS3 Not assessed: no validated functional assay, control data, or variant-specific experimental result demonstrated preserved function for c.75A>G (p.Val25=).

BS4 Not assessed: no informative affected or unaffected relatives with genotype and phenotype data are reported.

BP2 Not assessed: no pathogenic partner allele or documented cis/trans phase is reported for NM_000077.5:c.75A>G.

BP5 Not assessed: no established alternative molecular cause is documented to explain the patient's phenotype independently.

BP6 Not met: the exact ClinVar record has 0 expert-panel submissions despite non-expert Benign or Likely benign labels.

BP7 Not assessed: SpliceAI max delta is 0.006, but no evidence establishes that the synonymous position is not highly conserved.

N/A · 8 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.82963e-06; MAF= 0.00068%, 11/1610628 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.32616e-06; MAF= 0.00093%, 11/1179478 alleles, homozygotes = 0); grpmax FAF= 5e-06.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00068% · 11 / 1,610,628
0 hom · FAF 0.0005%

European (non-Finnish)

11 / 1,179,478

0.00093%

+ 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 / ?
0 hom

Not observed in any ancestry group.

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 Likely benign (3 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 827146)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

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

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 ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & references.

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.

PMID 25741868 ↗ · Richards S et al. · 2015 May CLINVAR · functional

Found

Structured finding pending for this record — see source link.

Applied to

→PM2 supporting

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

25645574 ↗ ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. CLINVAR

31672839 ↗ Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. 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

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

40674536 ↗ CDKN2A Cancer Predisposition. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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