9-21971160-C-T

Position:

• chr9-21971160-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000077.5(CDKN2A):​c.199G>A​(p.Gly67Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,442,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.57

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a repeat ANK 2 (size 28) in uniprot entity CDN2A_HUMAN there are 15 pathogenic changes around while only 3 benign (83%) in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.199G>A	p.Gly67Ser	missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.242G>A	p.Arg81Gln	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.199G>A	p.Gly67Ser	missense_variant	2/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.242G>A	p.Arg81Gln	missense_variant	2/3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000469 AC: 1 AN: 213440 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 119108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000597

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1442606 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717746

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000253

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.00000840 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 04, 2019	This missense variant replaces glycine with serine at codon 67 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies reported conflicting findings of abnormal CDK4 and CDK6 protein binding and altered subcellular localization but normal cell cycle (S-phase) arrest in transfected mammalian cells (PMID: 11518711, 20340136). This variant has been reported in two familial melanoma pedigrees (PMID: 11518711, 20340136). This variant has been identified in 1/213440 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 26, 2024	The p.G67S variant (also known as c.199G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 199. The glycine at codon 67 is replaced by serine, an amino acid with similar properties. Of note, this alteration is also known as c.242G>A (p.R81Q)in the p14(ARF) isoform. This alteration had been identified in familial melanoma patients (Goldstein AM et al. Cancer Res, 2006 Oct;66:9818-28; Goldstein AM et al. J Med Genet, 2007 Feb;44:99-106; Kannengiesser C et al. Genes Chromosomes Cancer, 2003 Nov;38:265-8). This alteration has been shown to segregate with disease in one family (Holland EA et al. Genes Chromosomes Cancer, 1999 Aug;25:339-48). Protein functional studies have shown that this variant has reduced CDK4/6 binding (McKenzie HA et al. Hum Mutat, 2010 Jun;31:692-701); however it retains normal cell cycle activity (Rizos H et al. J. Biol. Chem., 2001 Nov;276:41424-34; Miller PJ et al. Hum Mutat, 2011 Aug;32:900-11). Based on internal structural analysis, G67S is more disruptive to the CDKN2A-CDK4 interaction interface than several nearby pathogenic variants (Byeon IJ et al. Mol Cell, 1998 Feb;1:421-31; Kannengiesser C et al. Hum Mutat, 2009 Apr;30:564-74; Li J et al. Biochemistry, 2011 Jun;50:5566-82). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;T;.;.;.;.;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.041	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.7	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.66
MutPred		0.81		Gain of glycosylation at G67 (P = 0.0155);Gain of glycosylation at G67 (P = 0.0155);.;Gain of glycosylation at G67 (P = 0.0155);.;.;.;.;
MVP		0.99
MPC		1.2
ClinPred		0.76	D
GERP RS		5.8
Varity_R		0.51
gMVP		0.90

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: rs758389471; hg19: chr9-21971159; COSMIC: COSV58685808; COSMIC: COSV58685808;