9-21975018-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:3O:1

Conservation

PhyloP100: -0.170

Variant links:

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 links:

ENSG00000264545 (HGNC:):

ENSG00000264545 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 link	c.194-3810G>A		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2	Q8N726-1
CDKN2A	NM_000077.5 link	c.-191G>A		upstream_gene_variant		ENST00000304494.10	NP_000068.1	P42771-1K7PML8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2 link	c.194-3810G>A		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1		Q8N726-1
CDKN2A	ENST00000304494.10 link	c.-191G>A		upstream_gene_variant		1	NM_000077.5	ENSP00000307101.5		P42771-1

Frequencies

GnomAD3 genomes

AF:

0.504

AC:

76522

AN:

151970

Hom.:

21594

Cov.:

show subpopulations

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.:

AF XY:

0.610

AC XY:

361760

AN XY:

593052

show subpopulations

Gnomad4 AFR exome

AF:

0.212

Gnomad4 AMR exome

AF:

0.454

Gnomad4 ASJ exome

AF:

0.579

Gnomad4 EAS exome

AF:

0.681

Gnomad4 SAS exome

AF:

0.617

Gnomad4 FIN exome

AF:

0.662

Gnomad4 NFE exome

AF:

0.619

Gnomad4 OTH exome

AF:

0.590

GnomAD4 genome

AF:

0.503

AC:

76522

AN:

152088

Hom.:

21585

Cov.:

AF XY:

0.508

AC XY:

37727

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.232

Gnomad4 AMR

AF:

0.476

Gnomad4 ASJ

AF:

0.582

Gnomad4 EAS

AF:

0.648

Gnomad4 SAS

AF:

0.617

Gnomad4 FIN

AF:

0.663

Gnomad4 NFE

AF:

0.626

Gnomad4 OTH

AF:

0.500

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:1Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over