9-21974763-C-T

Variant names:

• chr9-21974763-C-T
• rs1554656491
• NM_000077.5:c.65G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000077.5(CDKN2A):​c.65G>A​(p.Arg22Gln) 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 1,456,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign 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: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.182

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]

ENSG00000264545 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a repeat ANK 1 (size 29) in uniprot entity CDN2A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1481137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.65G>A	p.Arg22Gln	missense_variant	Exon 1 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-3555G>A		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.65G>A	p.Arg22Gln	missense_variant	Exon 1 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.194-3555G>A		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456978 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725024

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: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 08, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 22 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. -

Familial melanoma Uncertain:1

Mar 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 22 of the CDKN2A (p16INK4a) protein (p.Arg22Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. ClinVar contains an entry for this variant (Variation ID: 491581). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	Benign	0.12
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.067	N
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.84	T
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N;.;N
REVEL	Benign	0.20
Sift	Benign	0.21	T;.;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.13	B;.;.
Vest4		0.13
MutPred		0.34		Loss of methylation at R22 (P = 0.012);Loss of methylation at R22 (P = 0.012);Loss of methylation at R22 (P = 0.012);
MVP		0.76
MPC		0.46
ClinPred		0.093	T
GERP RS		-3.0
Varity_R		0.11
gMVP		0.81

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: rs1554656491; hg19: chr9-21974762;