rs3088440

chr9-21968160-G-A

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.*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
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -1.05

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=-0.93).
• 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_single_submitter, 1 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	c.*69C>T		3_prime_UTR_variant	3/3	ENST00000304494.10
CDKN2A	NM_058195.4	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	c.*69C>T		3_prime_UTR_variant	3/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.*184C>T		3_prime_UTR_variant	3/3	1	NM_058195.4

Frequencies

GnomAD3 genomes AF: 0.132 AC: 19950 AN: 151564 Hom.: 1601 Cov.: 32

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.: 17 AF XY: 0.105 AC XY: 64948 AN XY: 617492

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.: 32 AF XY: 0.135 AC XY: 10026 AN XY: 74098

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:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

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

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	-0.93
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

Other links and lift over

dbSNP: rs3088440; hg19: chr9-21968159; COSMIC: COSV58724777; COSMIC: COSV58724777;