rs759871071

Positions:

• chr9-21974826-A-C
• chr9-21974826-A-G
• chr9-21974826-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000304494.10(CDKN2A):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,078 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDKN2A ENST00000304494.10 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.800

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.2T>G	p.Met1?	start_lost	1/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-3618T>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.2T>G	p.Met1?	start_lost	1/3	1	NM_000077.5	ENSP00000307101	P2
CDKN2A	ENST00000579755.2	c.194-3618T>G		intron_variant		1	NM_058195.4	ENSP00000462950

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1440078 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715822

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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	Apr 10, 2024	The p.M1? variant (also known as c.2T>G), located in coding exon 1 of the CDKN2A gene, results from a T to G substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an alternate in-frame methionine nine amino acids from the initiation site and the significance of the N-terminus for this protein is not well established. This variant has been reported in the literature in an individual with non-familial melanoma (Ghiorzo P et al. Exp. Dermatol., 2012 Sep;21:718-20). This amino acid position is not well conserved on limited sequence alignment. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2020	This variant affects the initiator methionine in the CDKN2A (p16INK4A) mRNA. Another in-frame methionine is located at codon 9, which may be able to rescue translation intiation. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with cutaneous melanoma in the literature (PMID: 22804906). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 23, 2023

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. ClinVar contains an entry for this variant (Variation ID: 660169). Disruption of the initiator codon has been observed in individual(s) with cutaneous melanoma (PMID: 22804906). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the CDKN2A (p16INK4a) mRNA. The next in-frame methionine is located at codon 9. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	14
DANN	Benign	0.84
DEOGEN2	Benign	0.065	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PROVEAN	Benign	0.21	N;.;N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0	B;.;.
Vest4		0.57
MutPred		0.54		Loss of catalytic residue at M1 (P = 0.0148);Loss of catalytic residue at M1 (P = 0.0148);Loss of catalytic residue at M1 (P = 0.0148);
MVP		0.80
ClinPred		0.052	T
GERP RS		-2.5
Varity_R		0.68
gMVP		0.74

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: rs759871071; hg19: chr9-21974825;