rs1554654052

Positions:

• chr9-21971075-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000077.5(CDKN2A):​c.283del​(p.Val95TrpfsTer51) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V95V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.182

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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. There are 39 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21971075-AC-A is Pathogenic according to our data. Variant chr9-21971075-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 463493.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-21971075-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.283del	p.Val95TrpfsTer51	frameshift_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.326del	p.Gly109ValfsTer63	frameshift_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.283del	p.Val95TrpfsTer51	frameshift_variant	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.326del	p.Gly109ValfsTer63	frameshift_variant	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 27, 2017

For these reasons, this variant has been classified as Pathogenic. A different frameshift variant located downstream of this variant (p.Glu120Serfs*26) has been determined to be pathogenic (PMID: 9439668, 20539244, 20653773, 25780468, 26681309). This suggests that deletion of this region of the CDKN2A protein is causative of disease. This variant has been reported in the literature in an individual affected with pancreatic cancer (PMID: 21150883). This sequence change deletes 1 nucleotide from exon 2 of the CDKN2A mRNA (c.283delG), causing a frameshift at codon 95. This creates a premature translational stop signal in the penultimate exon of the CDKN2A mRNA (p.Val95Trpfs*51). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 62 amino acids (~39%) of the CDKN2A protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554654052; hg19: chr9-21971074;