chr9-21971183-A-G

Position:

• chr9-21971183-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000077.5(CDKN2A):​c.176T>C​(p.Val59Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.84

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 6 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, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.176T>C	p.Val59Ala	missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.219T>C	p.Ser73Ser	synonymous_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.176T>C	p.Val59Ala	missense_variant	2/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.219T>C	p.Ser73Ser	synonymous_variant	2/3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19571771, 21893440, 20653773, 22841127, 26681309, 12700603, 19799798, 15146471, 9425228, 21507037, 28146043, 30395287) -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2023

The p.V59A variant (also known as c.176T>C), located in coding exon 2 of the CDKN2A gene, results from a T to C substitution at nucleotide position 176. The valine at codon 59 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 01, 2021

This variant is not present in population databases (ExAC no frequency). 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. This variant disrupts the p.Val59 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9425228, 12700603, 15146471, 19571771, 19799798, 20653773, 21893440, 22841127, 26681309). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with melanoma (PMID: 21507037, 28146043). This sequence change replaces valine with alanine at codon 59 of the CDKN2A (p16INK4a) protein (p.Val59Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;.;.;.;.;T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;T;.;T;.;T;T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.56	T
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.4	D;.;.;D;.;.;.;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.0020	D;T;D;D;D;D;D;D
Polyphen		0.93	P;.;.;.;.;.;.;.
Vest4		0.59
MutPred		0.76		Loss of catalytic residue at V59 (P = 0.004);Loss of catalytic residue at V59 (P = 0.004);.;Loss of catalytic residue at V59 (P = 0.004);.;.;.;.;
MVP		0.97
MPC		1.3
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.48
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-21971182;