9-21971160-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 5.57

Variant links:

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 links:

ENSG00000264545 (HGNC:):

ENSG00000264545 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 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

PP5

Variant 9-21971160-C-T is Pathogenic according to our data. Variant chr9-21971160-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 925139.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}. Variant chr9-21971160-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5 link	c.199G>A	p.Gly67Ser	missense_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1	P42771-1K7PML8
CDKN2A	NM_058195.4 link	c.242G>A	p.Arg81Gln	missense_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2	Q8N726-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10 link	c.199G>A	p.Gly67Ser	missense_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5		P42771-1
CDKN2A	ENST00000579755.2 link	c.242G>A	p.Arg81Gln	missense_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1		Q8N726-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000469

AC:

AN:

213440

Hom.:

AF XY:

0.00

AC XY:

AN XY:

119108

show subpopulations

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:

AN:

1442606

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717746

show subpopulations

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.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000840

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Apr 10, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). 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. Functional studies reported conflicting findings of abnormal CDK4 and CDK6 protein binding and altered subcellular localization but normal cell cycle arrest in transfected mammalian cells (PMID: 11518711, 20340136, 21462282). This variant has been reported in two familial melanoma pedigrees and shown to segregate with disease (PMID: 10398427, 14506702). 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. -

Aug 26, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 67 of the CDKN2A (p16INK4a) protein (p.Gly67Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 10398427, 12175554, 14506702, 19260062, 10390011). It has also been observed to segregate with disease in related individuals. This variant is also known as c.242G>A (p.Arg81Gln) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 925139). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on CDKN2A (p16INK4a) function (PMID: 11518711, 19260062, 20340136, 21462282). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

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

LIST_S2

Pathogenic

0.99

D;D;.;D;.;D;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.041

PrimateAI

Uncertain

0.63

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over