9-21968200-C-G

Position:

chr9-21968200-C-G

Variant summary

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

The NM_000077.5(CDKN2A):c.*29G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.867 in 1,609,364 control chromosomes in the GnomAD database, including 605,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 56366 hom., cov: 28)

Exomes 𝑓: 0.87 ( 548771 hom. )

Consequence

CDKN2A
NM_000077.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: -2.62

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 9-21968200-C-G is Benign according to our data. Variant chr9-21968200-C-G is described in ClinVar as [Benign]. Clinvar id is 873162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21968200-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5 linkuse as main transcript	c.*29G>C		3_prime_UTR_variant	3/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4 linkuse as main transcript	c.*144G>C		3_prime_UTR_variant	3/3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10 linkuse as main transcript	c.*29G>C		3_prime_UTR_variant	3/3	1	NM_000077.5	ENSP00000307101	P2	P42771-1
CDKN2A	ENST00000579755.2 linkuse as main transcript	c.*144G>C		3_prime_UTR_variant	3/3	1	NM_058195.4	ENSP00000462950		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.861

AC:

130666

AN:

151730

Hom.:

56326

Cov.:

show subpopulations

Gnomad AFR

AF:

0.837

Gnomad AMI

AF:

0.881

Gnomad AMR

AF:

0.885

Gnomad ASJ

AF:

0.822

Gnomad EAS

AF:

0.979

Gnomad SAS

AF:

0.939

Gnomad FIN

AF:

0.866

Gnomad MID

AF:

0.813

Gnomad NFE

AF:

0.857

Gnomad OTH

AF:

0.857

GnomAD3 exomes

AF:

0.882

AC:

221546

AN:

251310

Hom.:

97941

AF XY:

0.881

AC XY:

119615

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.835

Gnomad AMR exome

AF:

0.919

Gnomad ASJ exome

AF:

0.828

Gnomad EAS exome

AF:

0.978

Gnomad SAS exome

AF:

0.931

Gnomad FIN exome

AF:

0.871

Gnomad NFE exome

AF:

0.855

Gnomad OTH exome

AF:

0.867

GnomAD4 exome

AF:

0.867

AC:

1263961

AN:

1457518

Hom.:

548771

Cov.:

AF XY:

0.868

AC XY:

629660

AN XY:

725386

show subpopulations

Gnomad4 AFR exome

AF:

0.829

Gnomad4 AMR exome

AF:

0.915

Gnomad4 ASJ exome

AF:

0.825

Gnomad4 EAS exome

AF:

0.981

Gnomad4 SAS exome

AF:

0.929

Gnomad4 FIN exome

AF:

0.873

Gnomad4 NFE exome

AF:

0.859

Gnomad4 OTH exome

AF:

0.865

GnomAD4 genome

AF:

0.861

AC:

130763

AN:

151846

Hom.:

56366

Cov.:

AF XY:

0.863

AC XY:

64034

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.837

Gnomad4 AMR

AF:

0.885

Gnomad4 ASJ

AF:

0.822

Gnomad4 EAS

AF:

0.979

Gnomad4 SAS

AF:

0.939

Gnomad4 FIN

AF:

0.866

Gnomad4 NFE

AF:

0.857

Gnomad4 OTH

AF:

0.859

Alfa

AF:

0.855

Hom.:

10219

Bravo

AF:

0.861

Asia WGS

AF:

0.941

AC:

3274

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

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

Squamous cell lung carcinoma

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing;in vivo

Faculté Pluridciplinaire Nador, Université Mohamed Premier

May 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.083

DANN

Benign

0.65

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