About CDKN2A
No gene-level summary was recorded for this case.
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.No gene-level summary was recorded for this case.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
No pathogenic criterion marked as applied in the recorded assessment.
One homozygote for this variant is observed in gnomAD v4.1 (153 alleles total, 1 homozygous individual). CDKN2A is a well-established dominant melanoma susceptibility gene; homozygous pathogenic variants would be expected to result in severe or lethal phenotypes. The observation of a homozygote in a large population database is inconsistent with a high-penetrance pathogenic variant and supports a benign interpretation.
Well-established functional studies demonstrate no damaging effect on protein function. Parry & Peters (PMID:8668202) showed that the amino- and carboxy-terminal domains of p16, outside the ankyrin repeats, are dispensable for function. Schraml et al. (PMID:11159196) specifically reported that the 24-bp deletion mutant was functionally normal for CDK4 binding, citing Monzon et al. (1998). Both the 24-bp deletion and the reciprocal 24-bp insertion lie outside the ankyrin-repeat region critical for CDK4/CDK6 interaction.
The 24-bp deletion occurs within a repetitive sequence region at the 5' end of CDKN2A exon 1. Schraml et al. (PMID:11159196) documented 25 possible deletion variants leading to the same sequence alteration within this repeat region, and noted that both 24-bp deletions and duplications occur in this unstable repeat. In-frame deletions in repetitive regions without known function meet BP3.
SpliceAI predicts no significant splice impact (max delta score = 0.06). While REVEL and BayesDel are not applicable to deletions, the low SpliceAI score provides computational evidence against a splicing defect. However, this represents a single line of computational evidence, limiting strength to supporting.
No source classification-combination explanation was recorded.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 153 / 1,606,464 alleles. Recorded AF 9.52402e-05. Recorded homozygote count 1.
This variant is present in gnomAD v2.1 (AF= 0.000135726; MAF= 0.01357%, 36/265240 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000512762; MAF= 0.05128%, 18/35104 alleles, homozygotes = 0); grpmax FAF= 0.00033868.
Absent from gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.060. Refer to the recorded PP3/BP4 rationale for interpretation.
13 Uncertain significance · 1 Likely benign.
In progress — evidence not uploaded yet.
This variant has previously been reported in somatic cancers (COSMIC; COSV58687620, n = 11 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 10 not met · 7 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
NM_000077.4:c.9_32del (p.Ala4_Pro11del) is an in-frame 24-bp deletion removing 8 amino acids from the N-terminus of p16 in CDKN2A.
This deletion does not qualify as a null variant under the ClinGen SVI PVS1 framework (PMC6185798) and PVS1 is not applicable.
The variant is present in gnomAD v2.1 at 36/265,240 alleles (AF=0.0136%) and in gnomAD v4.1 at 153/1,606,464 alleles (AF=0.0095%) including one homozygote. These population frequencies are inconsistent with a high-penetrance pathogenic variant in a dominant cancer predisposition gene.
One homozygote is observed in gnomAD v4.1 (BS2_supporting). Homozygosity for a pathogenic CDKN2A variant would be expected to produce a severe phenotype, and its presence in a population database argues against high penetrance pathogenicity.
Functional studies demonstrate no damaging effect on p16 function. The N-terminal domain outside the ankyrin repeats is dispensable (PMID:8668202), and the specific 24-bp deletion mutant shows normal CDK4 binding (PMID:11159196) (BS3_supporting).
The deletion occurs within a repetitive sequence region of CDKN2A exon 1 with 25 possible deletion variants yielding the same sequence alteration; both deletions and duplications have been documented at this site (BP3_supporting).
SpliceAI predicts no significant splicing impact (max delta score = 0.06) (BP4_supporting).
The variant has been observed in melanoma-affected families (PMID:10070944, PMID:16905682, PMID:25780468) and is reported as a variant of uncertain significance by 13 clinical laboratories in ClinVar, with one laboratory classifying it as likely benign. No expert panel has adjudicated this variant.
Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): the criteria met are BS2_supporting, BS3_supporting, BP3_supporting, and BP4_supporting. Four supporting benign criteria would satisfy 'Likely Benign' classification (≥2 supporting benign). However, the presence of a homozygous individual in gnomAD, taken together with functional evidence of normal protein activity and location in a repetitive region, supports a classification of Likely Benign.
No criteria match.
No further detail was recorded.
No further detail was recorded.
No further detail was recorded.
No further detail was recorded.
No further detail was recorded.
Every interpreted variant in CDKN2A, mapped onto the exon structure of NM_000077.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Admixed American54 / 59,888 | 0.00091 hom |
| Middle Eastern1 / 6,022 | 0.00017 |
| East Asian4 / 44,836 | 8.9e-05 |
| Remaining individuals5 / 62,342 | 8e-05 |
| European (non-Finnish)84 / 1,179,054 | 7.1e-05 |
| South Asian5 / 90,940 | 5.5e-05 |
| Admixed American18 / 35,104 | 0.00051 |
| Remaining individuals2 / 6,928 | 0.00029 |
| East Asian2 / 19,354 | 0.0001 |
| European (non-Finnish)12 / 119,780 | 0.0001 |
| South Asian2 / 30,316 | 6.6e-05 |
This variant is present in gnomAD v4.1 (AF= 9.52402e-05; MAF= 0.00952%, 153/1606464 alleles, homozygotes = 1) and has highest observed frequency in the Admixed American population (AF= 0.000901683; MAF= 0.09017%, 54/59888 alleles, homozygotes = 1); grpmax FAF= 0.00070967.
This variant is present in gnomAD v2.1 (AF= 0.000135726; MAF= 0.01357%, 36/265240 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000512762; MAF= 0.05128%, 18/35104 alleles, homozygotes = 0); grpmax FAF= 0.00033868.
Absent from gnomAD-Canada v1.0.
No further detail was recorded.
In progress — evidence not uploaded yet.
8 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.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 9.52402e-05; MAF= 0.00952%, 153/1606464 alleles, homozygotes = 1) and has highest observed frequency in the Admixed American population (AF= 0.000901683; MAF= 0.09017%, 54/59888 alleles, homozygotes = 1); grpmax FAF= 0.00070967.
This variant is present in gnomAD v2.1 (AF= 0.000135726; MAF= 0.01357%, 36/265240 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000512762; MAF= 0.05128%, 18/35104 alleles, homozygotes = 0); grpmax FAF= 0.00033868.
Absent from gnomAD-Canada v1.0.
In progress — evidence not uploaded yet.
In progress — evidence not uploaded yet.
In progress — evidence not uploaded yet.
In progress — evidence not uploaded yet.
This variant does not lie in a statistically significant hotspot.
In progress — evidence not uploaded yet.