rs121913388

Positions:

• chr9-21971121-G-A
• chr9-21971121-G-C
• chr9-21971121-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.238C>T​(p.Arg80Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R80R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDKN2A NM_000077.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 1.26

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 19 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 67 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-21971121-G-A is Pathogenic according to our data. Variant chr9-21971121-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21971121-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.238C>T	p.Arg80Ter	stop_gained	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.281C>T	p.Pro94Leu	missense_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.238C>T	p.Arg80Ter	stop_gained	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.281C>T	p.Pro94Leu	missense_variant	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451466 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722490

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 8668202, 11687599, 8153634, 29152076, 10854221, 15195137, 18205010, 27415609, 29917141, 23939042, 31775759, 30039340, 9529249, 9653180, 16173922, 31382929) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 08, 2020	The p.R80* pathogenic mutation (also known as c.238C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 238. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant changes 1 nucleotide in exon 2 of the CDKN2A gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDKN2A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Familial melanoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 19, 2023	The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. For these reasons, this variant has been classified as Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its association with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear. ClinVar contains an entry for this variant (Variation ID: 9409). This variant is also known as c.281C>T p.Pro94Leu in the CDKN2A (p14ARF) transcript. This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 31382929). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg80*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 23, 2023	Variant summary: CDKN2A c.238C>T (p.Arg80X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. At least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant was absent in 229380 control chromosomes (gnomAD). c.238C>T has been reported in the literature in individuals affected with Multiple Primary Melanomas (Puig_2015, Casula_2019). At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in loss of binding to Cdk4 and Cdk6 (Parry_1996). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=4) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Lip and oral cavity carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Sciences, Banaras Hindu University

Apr 30, 2019

- -

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

risk factor, no assertion criteria provided

literature only

OMIM

Apr 15, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.64	.;T
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-7.9	.;D
REVEL	Uncertain	0.48
Sift	Benign	0.084	.;T
Sift4G	Pathogenic	0.0	D;D
Vest4		0.27
MVP		0.98
ClinPred		0.98	D
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.55		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: rs121913388; hg19: chr9-21971120; COSMIC: COSV58682746; COSMIC: COSV58682746;