chr9-21975018-C-T

Variant names:

• chr9-21975018-C-T
• rs3814960
• NM_058195.4:c.194-3810G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_058195.4(CDKN2A):​c.194-3810G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 1,380,732 control chromosomes in the GnomAD database, including 252,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (21585 hom., cov: 32)
  • Exomes 𝑓: 0.61 (231157 hom.)
• Consequence: CDKN2A NM_058195.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3 O:1
• Conservation: PhyloP100: -0.170
• Publications: 26 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 9-21975018-C-T is Benign according to our data. Variant chr9-21975018-C-T is described in ClinVar as Benign. ClinVar VariationId is 873184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.194-3810G>A		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2
CDKN2A	NM_000077.5	c.-191G>A		upstream_gene_variant		ENST00000304494.10	NP_000068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2	c.194-3810G>A		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1
CDKN2A	ENST00000304494.10	c.-191G>A		upstream_gene_variant		1	NM_000077.5	ENSP00000307101.5

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76522 AN: 151970 Hom.: 21594 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.503

GnomAD4 exome AF: 0.610 AC: 749192 AN: 1228644 Hom.: 231157 Cov.: 40 AF XY: 0.610 AC XY: 361760 AN XY: 593052

African (AFR) AF: 0.212 AC: 5041 AN: 23730

American (AMR) AF: 0.454 AC: 5749 AN: 12660

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 9941 AN: 17158

East Asian (EAS) AF: 0.681 AC: 20110 AN: 29528

South Asian (SAS) AF: 0.617 AC: 33068 AN: 53570

European-Finnish (FIN) AF: 0.662 AC: 20365 AN: 30740

Middle Eastern (MID) AF: 0.576 AC: 1973 AN: 3428

European-Non Finnish (NFE) AF: 0.619 AC: 622968 AN: 1007056

Other (OTH) AF: 0.590 AC: 29977 AN: 50774

GnomAD4 genome AF: 0.503 AC: 76522 AN: 152088 Hom.: 21585 Cov.: 32 AF XY: 0.508 AC XY: 37727 AN XY: 74326

African (AFR) AF: 0.232 AC: 9645 AN: 41490

American (AMR) AF: 0.476 AC: 7274 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2019 AN: 3468

East Asian (EAS) AF: 0.648 AC: 3330 AN: 5138

South Asian (SAS) AF: 0.617 AC: 2974 AN: 4822

European-Finnish (FIN) AF: 0.663 AC: 7017 AN: 10590

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.626 AC: 42552 AN: 67980

Other (OTH) AF: 0.500 AC: 1054 AN: 2108

Alfa AF: 0.592 Hom.: 7136

Bravo AF: 0.473

Asia WGS AF: 0.584 AC: 2036 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: 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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Squamous cell lung carcinoma Uncertain:1

May 05, 2020

Faculté Pluridciplinaire Nador, Université Mohamed Premier

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing;in vivo

- -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.9
DANN	Benign	0.88
PhyloP100		-0.17
PromoterAI		-0.024	Neutral
Mutation Taster		=299/1	polymorphism (auto)

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: rs3814960; hg19: chr9-21975017; COSMIC: COSV58720858; COSMIC: COSV58720858;