rs1554653915

Positions:

• chr9-21970965-CGCGCAGGTACCGT-CCGCATC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000077.5(CDKN2A):​c.381_393delACGGTACCTGCGCinsGATGCG​(p.Arg128fs) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 frameshift, missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.30

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]

CDKN2A (HGNC:):

ACMG classification

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 0.191 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21970966-GCGCAGGTACCGT-CGCATC is Pathogenic according to our data. Variant chr9-21970966-GCGCAGGTACCGT-CGCATC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 463503.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.381_393delACGGTACCTGCGCinsGATGCG	p.Arg128fs	frameshift_variant, missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.*25_*37delACGGTACCTGCGCinsGATGCG		3_prime_UTR_variant	2/3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.381_393delACGGTACCTGCGCinsGATGCG	p.Arg128fs	frameshift_variant, missense_variant	2/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755	c.*25_*37delACGGTACCTGCGCinsGATGCG		3_prime_UTR_variant	2/3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial melanoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2017

In summary, this variant is a novel truncating variant that deletes an important region of the CDKN2A protein. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A downstream variant (p.Asp153Tyr) has been determined to be pathogenic by causing partial exon 2 skipping, resulting in the deletion of the final 24 amino acids of exon 2 and a frameshift in exon 3 (PMID: 14508519, 12853981, 14508519). This suggests that disruption of this region of the CDKN2A protein is causative of disease. This variant has not been reported in the literature in individuals with a CDKN2A-related disease. This sequence change deletes 13 and inserts 6 nucleotides in exon 2 of the CDKN2A mRNA (c.381_393delinsGATGCG), causing a frameshift at codon 128. This creates a premature translational stop signal in the penultimate exon of the CDKN2A mRNA (p.Arg128Cysfs*16). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acids of the CDKN2A protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554653915; hg19: chr9-21970965;