Variant 9-21968160-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000077.5(CDKN2A):c.*69C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,372,012 control chromosomes in the GnomAD database, including 10,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1606 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9083 hom. )

Consequence

CDKN2A
NM_000077.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.05

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:

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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=-0.93).

BP6

Variant 9-21968160-G-A is Benign according to our data. Variant chr9-21968160-G-A is described in ClinVar as [Benign]. Clinvar id is 1227284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21968160-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5 linkuse as main transcript	c.*69C>T		3_prime_UTR_variant	3/3	ENST00000304494.10
CDKN2A	NM_058195.4 linkuse as main transcript	c.*184C>T		3_prime_UTR_variant	3/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10 linkuse as main transcript	c.*69C>T		3_prime_UTR_variant	3/3	1	NM_000077.5	P2	P42771-1
CDKN2A	ENST00000579755.2 linkuse as main transcript	c.*184C>T		3_prime_UTR_variant	3/3	1	NM_058195.4		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

19950

AN:

151564

Hom.:

1601

Cov.:

show subpopulations

Gnomad AFR

AF:

0.174

Gnomad AMI

AF:

0.0396

Gnomad AMR

AF:

0.253

Gnomad ASJ

AF:

0.0885

Gnomad EAS

AF:

0.125

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0845

Gnomad OTH

AF:

0.121

GnomAD4 exome

AF:

0.106

AC:

129199

AN:

1220332

Hom.:

9083

Cov.:

AF XY:

0.105

AC XY:

64948

AN XY:

617492

show subpopulations

Gnomad4 AFR exome

AF:

0.173

Gnomad4 AMR exome

AF:

0.365

Gnomad4 ASJ exome

AF:

0.0984

Gnomad4 EAS exome

AF:

0.105

Gnomad4 SAS exome

AF:

0.159

Gnomad4 FIN exome

AF:

0.112

Gnomad4 NFE exome

AF:

0.0861

Gnomad4 OTH exome

AF:

0.113

GnomAD4 genome

AF:

0.132

AC:

19992

AN:

151680

Hom.:

1606

Cov.:

AF XY:

0.135

AC XY:

10026

AN XY:

74098

show subpopulations

Gnomad4 AFR

AF:

0.175

Gnomad4 AMR

AF:

0.253

Gnomad4 ASJ

AF:

0.0885

Gnomad4 EAS

AF:

0.125

Gnomad4 SAS

AF:

0.166

Gnomad4 FIN

AF:

0.106

Gnomad4 NFE

AF:

0.0845

Gnomad4 OTH

AF:

0.120

Alfa

AF:

0.103

Hom.:

356

Bravo

AF:

0.146

Asia WGS

AF:

0.161

AC:

558

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.32

DANN

Benign

0.70

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