rs730881677

Positions:

• chr9-21971209-C-A
• chr9-21971209-C-G
• chr9-21971209-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_000077.5(CDKN2A):​c.151-1G>T variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.27

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 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-21971209-C-A is Pathogenic according to our data. Variant chr9-21971209-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 422058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.151-1G>T		splice_acceptor_variant		ENST00000304494.10
CDKN2A	NM_058195.4	c.194-1G>T		splice_acceptor_variant		ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.151-1G>T		splice_acceptor_variant		1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.194-1G>T		splice_acceptor_variant		1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2016	This pathogenic variant is denoted CDKN2A c.151-1G>T or IVS1-1G>T and consists of a G>T nucleotide substitution at the -1 position of intron 1 of the CDKN2A gene. This variant destroys a canonical splice acceptor 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. Although this variant has not, to our knowledge, been reported in the literature, another variant at the same position, CDKN2A c.151-1G>C, has been observed in at least three families with melanoma, dysplastic nevi, and a variety of other benign and malignant tumors, including several individuals with neurofibromas (Petronzelli 2001, Prowse 2003, Sargen 2016). Additionally, the CDKN2A c.151-1G>C variant has been shown on RT-PCR studies to result in skipping of exon 2 (Petronzelli 2001, Prowse 2003). Based on the current evidence, we consider CDKN2A c.151-1G>T to be pathogenic. -
not provided, no classification provided	in vitro	MutSpliceDB: a database of splice sites variants effects on splicing, NIH	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2021

The c.151-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 2 of the CDKN2A gene. This alteration has been reported in a cohort of melanoma-prone families (Taylor NJ et al. J Invest Dermatol, 2017 12;137:2606-2612). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.78		Position offset: -18
DS_AL_spliceai		1.0		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs730881677; hg19: chr9-21971208; COSMIC: COSV58695350; COSMIC: COSV58695350;