9-21974703-T-C

Position:

• chr9-21974703-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The ENST00000304494.10(CDKN2A):​c.125A>G​(p.Asn42Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,208 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N42D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDKN2A ENST00000304494.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.61

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 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in ENST00000304494.10
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.125A>G	p.Asn42Ser	missense_variant	1/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-3495A>G		intron_variant		ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.125A>G	p.Asn42Ser	missense_variant	1/3	1	NM_000077.5	ENSP00000307101	P2
CDKN2A	ENST00000579755.2	c.194-3495A>G		intron_variant		1	NM_058195.4	ENSP00000462950

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461208 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726920

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CDKN2A-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2024

The CDKN2A c.125A>G variant is predicted to result in the amino acid substitution p.Asn42Ser. To our knowledge, this variant has not been reported in the literature or in gnomAD, indicating this variant is rare. This variant is interpreted as a variant of uncertain significance by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/406711/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 02, 2021

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2022

The p.N42S variant (also known as c.125A>G), located in coding exon 1 of the CDKN2A gene, results from an A to G substitution at nucleotide position 125. The asparagine at codon 42 is replaced by serine, an amino acid with highly 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

Nov 27, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 42 of the CDKN2A (p16INK4a) protein (p.Asn42Ser). 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: 406711). 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. 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	0.30
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.47	T;T;.
Eigen	Benign	0.15
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	-0.099	T
MutationTaster	Benign	1.0	D;D;D;D;D;N;N;N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.3	D;.;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D;.;D
Sift4G	Benign	0.071	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.60
MutPred		0.44		Gain of glycosylation at N42 (P = 0.0405);Gain of glycosylation at N42 (P = 0.0405);Gain of glycosylation at N42 (P = 0.0405);
MVP		0.93
MPC		1.1
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.51
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060501264; hg19: chr9-21974702;