chr9-21974641-C-G

Variant names:

• chr9-21974641-C-G
• rs45456595
• NM_000077.5:c.150+37G>C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP6 BS1 BS2

The NM_058197.5(CDKN2A):​c.187G>C​(p.Gly63Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,614,214 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (7 hom.)
• Consequence: CDKN2A NM_058197.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:13 O:1
• Conservation: PhyloP100: -2.00

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 Benign. Variant got -7 ACMG points.

• PM1: In a chain Cyclin-dependent kinase inhibitor 2A (size 155) in uniprot entity CDN2A_HUMAN there are 23 pathogenic changes around while only 8 benign (74%) in NM_058197.5
• BP6: Variant 9-21974641-C-G is Benign according to our data. Variant chr9-21974641-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41573.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=3, Likely_benign=4, not_provided=1}. Variant chr9-21974641-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00202 (308/152346) while in subpopulation NFE AF= 0.00325 (221/68028). AF 95% confidence interval is 0.0029. There are 0 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 308 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.150+37G>C		intron_variant	Intron 1 of 2	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-3433G>C		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.150+37G>C		intron_variant	Intron 1 of 2	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.194-3433G>C		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000940

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00202 AC: 507 AN: 250906 Hom.: 1 AF XY: 0.00213 AC XY: 289 AN XY: 135654

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00268 AC: 3921 AN: 1461868 Hom.: 7 Cov.: 32 AF XY: 0.00273 AC XY: 1984 AN XY: 727240

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.000599

Gnomad4 NFE exome AF: 0.00326

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74502

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00325

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00295 Hom.: 1

Bravo AF: 0.00237

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:13 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:7

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDKN2A: BS1, BS2 -

not specified Uncertain:2 Benign:1 Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in a family with melanoma, segregated in 2 individuals with atypical naevi and 1 with melanoma (Balogh 2012). MAF 0.3%. -

Feb 26, 2014

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Melanoma-pancreatic cancer syndrome Uncertain:1 Benign:2

Jun 20, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Jul 28, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 25, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G63R variant (also known as c.187G>C), located in coding exon 1 of the CDKN2A gene, results from a G to C substitution at nucleotide position 187. The glycine at codon 63 is replaced by arginine, an amino acid with dissimilar properties. A 47 year old male patient with malignant melanoma at age 43, from an Italian melanoma family, was reported to have this variant; this individual did not have the pathogenic CDKN2A p.R24P mutation that was present in other family members (Della Torre G et al. Br. J. Cancer. 2001 Sep;85:836-44). This variant has been reported in individuals with single primary melanoma and with multiple primary melanomas (Goldstein AM et al. J. Med. Genet. 2008 May;45:284-9; Pastorino L et al. Pigment Cell Melanoma Res. 2008 Dec;21:700-9; Bruno W et al. J. Am. Acad. Dermatol. 2016 Feb;74:325-32). However, in other studies this variant has been reported in both melanoma cases controls (Harland M et al. Hered Cancer Clin Pract. 2014 Nov;12:20). Using a minigene assay to investigate mRNA splicing regulation, this variant had a differential splicing pattern from wild-type (Balogh K et al. Br. J. Dermatol. 2012 Jul;167:131-3). This variant has also been reported in studies of patients with pancreatic cancer (Ghiorzo P et al. J. Med. Genet. 2012 Mar;49:164-70; Grant RC et al. Gastroenterology. 2015 Mar;148:556-64). It was also identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS ONE. 2014 Apr;9:e94554); and it was detected as a secondary finding in 4 out of 567 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing (Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91:97-108). This amino acid position is poorly conserved in available vertebrate species. Of note, this alteration is also designated as c.150+37G>C and IVS150+37G>C in the published literature. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

CDKN2A-related disorder Benign:1

Feb 07, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial melanoma Benign:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.1
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: -42

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45456595; hg19: chr9-21974640; COSMIC: COSV58719681; COSMIC: COSV58719681;