chr9-21994138-C-T

Position:

• chr9-21994138-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_058195.4(CDKN2A):​c.193+1G>A variant causes a splice donor 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 (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDKN2A NM_058195.4 splice_donor
• Scores: Splicing: ADA: 0.9533
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 3.21

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]

CDKN2B-AS1 (HGNC:34341): (CDKN2B antisense RNA 1) This gene is located within the CDKN2B-CDKN2A gene cluster at chromosome 9p21. The gene product is a functional RNA molecule that interacts with polycomb repressive complex-1 (PRC1) and -2 (PRC2), leading to epigenetic silencing of other genes in this cluster. This region is a significant genetic susceptibility locus for cardiovascular disease, and has also been linked to a number of other pathologies, including several cancers, intracranial aneurysm, type-2 diabetes, periodontitis, Alzheimer's disease, endometriosis, frailty in the elderly, and glaucoma. Multiple alternatively processed transcript variants have been detected, some of which may take the form of circular RNA molecules (PMID:21151960). [provided by RefSeq, May 2014]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.576
• PP5: Variant 9-21994138-C-T is Pathogenic according to our data. Variant chr9-21994138-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 406708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21994138-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_058195.4	c.193+1G>A		splice_donor_variant		ENST00000579755.2
CDKN2A	NM_001363763.2	c.-4+683G>A		intron_variant
CDKN2A	XM_047422597.1	c.-4+409G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000579755.2	c.193+1G>A		splice_donor_variant		1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2016

This variant is denoted CDKN2A c.193+1G>A or IVS1+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 1B of the of the CDKN2A gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Of note, the CDKN2A gene encodes the p16 protein and, using an alternate reading frame, the p14-ARF protein as well. As exon 1B is only used by the p14-ARF protein, CDKN2A c.193+1G>A will not affect the p16 protein. This variant has been reported in several individuals with a history of malignant melanoma and shown to segregate with disease in at least two families (Goldstein 2006, Harland 2005, Ghiorzo 2009, Binni 2010, Pedace 2011). We consider this CDKN2A c.193+1G>A to be pathogenic. -

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 14, 2020

This sequence change affects a donor splice site in intron 1 of the CDKN2A (p14ARF) gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial cutaneous melanoma (PMID: 21893440, 15856016, 20132244). It has also been observed to segregate with disease in related individuals. Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 15856016). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDKN2A (p14ARF) are known to be pathogenic (PMID: 11571653, 15856016, 17440112). For these reasons, this variant has been classified as Pathogenic. -

Melanoma, cutaneous malignant, susceptibility to, 2 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.67	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 13

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501262; hg19: chr9-21994137; COSMIC: COSV100845298; COSMIC: COSV100845298;