rs121913387

chr9-21971187-G-Achr9-21971187-G-Cchr9-21971187-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000077.5(CDKN2A):c.172C>T(p.Arg58Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R58R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN2A NM_000077.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.135

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 18 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 96 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21971187-G-A is Pathogenic according to our data. Variant chr9-21971187-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 376310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21971187-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.172C>T	p.Arg58Ter	stop_gained	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.215C>T	p.Pro72Leu	missense_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.172C>T	p.Arg58Ter	stop_gained	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.215C>T	p.Pro72Leu	missense_variant	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445040 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719266

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial melanoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 16, 2019	Loss-of-function variants in CDKN2A are known to be pathogenic (PMID: 15146471, 16905682). Experimental in vitro binding assays have shown that this variant disrupts the ability of p16INKA4a protein to bind to Cdk2 and Cdk4 (PMID: 8668202). An additional study in melanoma cells has shown that this variant reduces the ability of p14ARF to induce senescence and produce superoxide (PMID: 25370744). This variant has been observed in one individual and one family affected with melanoma (PMID: 18983535, 7987387). In addition, it has been reported to segregate with disease in that family (PMID: 7987387). This variant is also known as p16INK4a Arg50Ter in the literature. ClinVar contains an entry for this variant (Variation ID: 376310). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal at codon 58 of the p16INK4a protein (p.Arg58*). It is expected to result in an absent or disrupted p16INK4a protein product. Alternatively, this sequence gene replaces proline with leucine at codon 72 of the p14ARF protein. The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2023	Variant summary: CDKN2A c.172C>T (p.Arg58X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 219734 control chromosomes (gnomAD). c.172C>T has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma (e.g. Hussussian_1994). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 7987387). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Malignant tumor of urinary bladder Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Urology, Hospital Clinic de Barcelona

-

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2017

The p.R58* pathogenic mutation (also known as c.172C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 172. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation (also designated as "Arg50Ter" and "R58Ter") has been detected in multiple affected individuals from a familial melanoma kindred and shown to lack Cdk4 and Cdk6 binding in vitro (Hussussian CJ et al. Nat. Genet., 1994 Sep;8:15-21; Parry D et al. Mol. Cell. Biol., 1996 Jul;16:3844-52). In addition to the clinical data presented in the literature, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
Cadd	Pathogenic	35
Dann	Uncertain	1.0
DEOGEN2	Benign	0.092	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.27	N
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;D;N;N;N
Sift4G	Benign	0.067	T;T
Vest4		0.18
MVP		0.88
ClinPred		0.88	D
GERP RS		2.7

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: rs121913387; hg19: chr9-21971186; COSMIC: COSV58682666; COSMIC: COSV58682666;