rs200382984

chr9-21974721-G-Achr9-21974721-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_000077.5(CDKN2A):c.107C>T(p.Ala36Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,450,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A36S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.0740

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000077.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.3758341).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.107C>T	p.Ala36Val	missense_variant	1/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.194-3513C>T		intron_variant		ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.107C>T	p.Ala36Val	missense_variant	1/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.194-3513C>T		intron_variant		1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000441 AC: 1 AN: 226718 Hom.: 0 AF XY: 0.00000799 AC XY: 1 AN XY: 125140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000990

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1450760 Hom.: 0 Cov.: 32 AF XY: 0.00000555 AC XY: 4 AN XY: 721272

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: 0.00000541

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 13, 2022	The p.A36V variant (also known as c.107C>T), located in coding exon 1 of the CDKN2A gene, results from a C to T substitution at nucleotide position 107. The alanine at codon 36 is replaced by valine, an amino acid with similar properties. In a genome wide association study, this alteration was reported in a patient with childhood B-ALL and was not seen in any of the 10,448 non-ALL controls (Xu H et al, Nat Commun 2015 ; 6():7553). This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in several vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 28, 2020	This missense variant replaces alanine with valine at codon 36 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 been reported in an individual affected with acute lymphoblastic leukaemia (PMID: 26104880). This variant has been identified in 1/226718 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. -

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 36 of the CDKN2A (p16INK4a) protein (p.Ala36Val). This variant is present in population databases (no rsID available, gnomAD 0.001%). This missense change has been observed in individual(s) with childhood leukemia (PMID: 26104880). ClinVar contains an entry for this variant (Variation ID: 483324). 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 valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 34369425). 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	0.14
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.081	T;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.80	T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D;D;D;D;D;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Uncertain	0.36
Sift	Benign	0.86	T;.;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.79	P;.;.
Vest4		0.15
MutPred		0.76		Gain of catalytic residue at A36 (P = 0.0168);Gain of catalytic residue at A36 (P = 0.0168);Gain of catalytic residue at A36 (P = 0.0168);
MVP		0.99
MPC		0.47
ClinPred		0.14	T
GERP RS		-0.49
Varity_R		0.072
gMVP		0.89

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

LitVar

Other links and lift over

dbSNP: rs200382984; hg19: chr9-21974720;