9-21971029-C-T

Variant names:

• chr9-21971029-C-T
• rs121913389
• NM_000077.5:c.330G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.330G>A​(p.Trp110*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,202 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDKN2A NM_000077.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.403
• Publications: 29 publications found

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 Gene-Disease associations (from GenCC):

• melanoma, cutaneous malignant, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• melanoma-pancreatic cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial atypical multiple mole melanoma syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma and neural system tumor syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21971029-C-T is Pathogenic according to our data. Variant chr9-21971029-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 376303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.330G>A	p.Trp110*	stop_gained	Exon 2 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.373G>A	p.Gly125Arg	missense_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.330G>A	p.Trp110*	stop_gained	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.373G>A	p.Gly125Arg	missense_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454202 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723662

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5186

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111452

Other (OTH) AF: 0.00 AC: 0 AN: 60218

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 13, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W110* variant (also known as c.330G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 330. This changes the amino acid from a tryptophan to a stop codon within coding exon 2. This alteration has been detected in several melanoma patients, including a Greek patient diagnosed with multiple primary melanomas (Stratigos AJ et al. J Invest Dermatol. 2006 Feb;126:399-401; Nikolaou V et al. Br J Dermatol. 2011 Dec;165:1219-22; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration demonstrated reduced Cdk binding activity (Parry D et al. Mol Cell Biol. 1996 Jul;16:3844-52). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Mar 16, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This variant changes 1 nucleotide in exon 2 of the CDKN2A (p16INK4A) gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product missing the C-terminal sequence that encodes ankyrin repeat 4. This variant has been reported in two individuals affected with melanoma in the literature (PMID: 16374456, 21801156). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDKN2A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Lip and oral cavity carcinoma Pathogenic:1

Apr 30, 2019

Institute of Medical Sciences, Banaras Hindu University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial melanoma Pathogenic:1

May 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change creates a premature translational stop signal (p.Trp110*) in the CDKN2A (p16INK4a) gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKN2A (p16INK4a) are known to be pathogenic (PMID: 15146471, 16905682). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 16374456). This variant is also known as c.373G>A (p.Gly125Arg) in CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 376303). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CDKN2A (p16INK4a) function (PMID: 8668202). For these reasons, this variant has been classified as Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its association with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	38
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.63	.;T
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-0.96	T
PhyloP100		0.40
PROVEAN	Pathogenic	-6.2	.;D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.44
MVP		0.97
ClinPred		0.95	D
GERP RS		5.9
PromoterAI		0.0078	Neutral
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121913389; hg19: chr9-21971028; COSMIC: COSV58682827; COSMIC: COSV58682827;