chr9-21968200-C-G

Position:

• chr9-21968200-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter U:1 B:5
• Conservation: PhyloP100: -2.62

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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	UniProt
CDKN2A	NM_000077.5	c.*29G>C		3_prime_UTR_variant	3/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.*144G>C		3_prime_UTR_variant	3/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.*29G>C		3_prime_UTR_variant	3/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.*144G>C		3_prime_UTR_variant	3/3	1	NM_058195.4

Frequencies

GnomAD3 genomes AF: 0.861 AC: 130666 AN: 151730 Hom.: 56326 Cov.: 28

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

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.: 33 AF XY: 0.868 AC XY: 629660 AN XY: 725386

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.: 28 AF XY: 0.863 AC XY: 64034 AN XY: 74194

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:1 Benign:5

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:4

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+	-	- -
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	-	- -

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

- -

not provided Benign:1

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	-0.90
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

Other links and lift over

dbSNP: rs11515; hg19: chr9-21968199; COSMIC: COSV58682765; COSMIC: COSV58682765;