9-21970972-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_000077.5(CDKN2A):​c.387C>A​(p.Tyr129*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y129Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CDKN2A
NM_000077.5 stop_gained

Scores

2
3
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.47
Variant links:
Genes affected
CDKN2A (HGNC:1787): (cyclin dependent kinase inhibitor 2A) This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.178 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-21970972-G-T is Pathogenic according to our data. Variant chr9-21970972-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2146592.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDKN2ANM_000077.5 linkc.387C>A p.Tyr129* stop_gained Exon 2 of 3 ENST00000304494.10 NP_000068.1 P42771-1K7PML8
CDKN2ANM_058195.4 linkc.*31C>A 3_prime_UTR_variant Exon 2 of 3 ENST00000579755.2 NP_478102.2 Q8N726-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDKN2AENST00000304494.10 linkc.387C>A p.Tyr129* stop_gained Exon 2 of 3 1 NM_000077.5 ENSP00000307101.5 P42771-1
CDKN2AENST00000579755 linkc.*31C>A 3_prime_UTR_variant Exon 2 of 3 1 NM_058195.4 ENSP00000462950.1 Q8N726-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1459026
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
725936
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial melanoma Pathogenic:1
Jul 13, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change creates a premature translational stop signal (p.Tyr129*) in the CDKN2A (p16INK4a) gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKN2A (p16INK4a) are known to be pathogenic (PMID: 15146471, 16905682). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 12950144). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
38
DANN
Uncertain
1.0
Eigen
Uncertain
0.39
Eigen_PC
Benign
0.17
FATHMM_MKL
Uncertain
0.89
D
Vest4
0.86
GERP RS
0.024

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.50
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.50
Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-21970971; COSMIC: COSV58684005; COSMIC: COSV58684005; API