9-21971025-G-C

Position:

• chr9-21971025-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.334C>G​(p.Arg112Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,592 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.25

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]

CDKN2A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a chain Cyclin-dependent kinase inhibitor 2A (size 155) in uniprot entity CDN2A_HUMAN there are 42 pathogenic changes around while only 12 benign (78%) in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21971025-G-C is Pathogenic according to our data. Variant chr9-21971025-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 233484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.334C>G	p.Arg112Gly	missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.377C>G	p.Pro126Arg	missense_variant	2/3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.334C>G	p.Arg112Gly	missense_variant	2/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.377C>G	p.Pro126Arg	missense_variant	2/3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454592 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723878

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 06, 2024	The p.R112G variant (also known as c.334C>G), located in coding exon 2 of the CDKN2A gene, results from a C to G substitution at nucleotide position 334. The arginine at codon 112 is replaced by glycine, an amino acid with dissimilar properties. Of note, this alteration is also known as c.377C>G (p.P126R) in the p14(ARF) isoform. This variant was detected in a high-risk Australian melanoma family and segregated with disease in 3/3 affected individuals tested, including 2 relatives diagnosed in their twenties (Holland EA et al, Genes Chromosomes Cancer 1999 Aug; 25(4):339-48). This variant was reported in individuals with features consistent with Melanoma-pancreatic cancer syndrome (Ambry internal data). This alteration has also been reported in several additional melanoma families (Lang J et al. Br J Dermatol, 2005 Dec;153:1121-5; Maubec E et al. J Am Acad Dermatol, 2012 Dec;67:1257-64; Stolarova L et al. Biomedicines, 2020 Oct;8:). Functional analyses have shown p.R112G to be correlated with with decreased CDK4 binding in vivo, reduced expression, altered localization and impaired cell cycle arrest compared to wild type p16 (Rizos H et al, J. Biol. Chem. 2001 Nov; 276(44):41424-34; McKenzie HA et al. Hum Mutat, 2010 Jun;31:692-701; Miller PJ et al, Hum. Mutat. 2011 Aug; 32(8):900-11). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 27, 2022	The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces arginine with glycine at codon 112 of the CDKN2A (p16INK4A) protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant results in the reduced protein expression, altered subcellular localization and impaired p16INK4A binding to CDK4 (PMID: 11518711, 20340136). This variant has shown no or partial impact on the cell cycle arrest activity of the p16INK4A protein (PMID: 11518711, 12606942, 21462282). This variant has been reported in over 15 individuals and families affected with melanoma (PMID: 10398427, 12072543, 16307646, 16896043, 16905682, 17047042, 21462282, 22841127, 33050356). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Melanoma and neural system tumor syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 05, 2021

- -

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 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. This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 112 of the CDKN2A (p16INK4a) protein (p.Arg112Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma (PMID: 10398427, 12072543, 16307646, 16896043, 16905682, 17047042, 21462282, 22841127). It has also been observed to segregate with disease in related individuals. This variant is also known as c.377C>G (p.Pro126Arg) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 233484). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this variant affects protein function, which reduces binding to CDK4 and alters sub-cellular localization in vitro (PMID: 11518711, 20340136), but has conflicting results on cell-cycle arrest (PMID: 21462282, 12606942). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.47	.;T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.64	T
PROVEAN	Pathogenic	-4.5	.;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0070	.;D
Sift4G	Uncertain	0.013	D;D
Vest4		0.46
MVP		0.99
ClinPred		0.87	D
GERP RS		5.9

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: rs876660436; hg19: chr9-21971024; COSMIC: COSV58723857; COSMIC: COSV58723857;