9-21968160-G-A

Variant names:

• chr9-21968160-G-A
• rs3088440
• NM_000077.5:c.*69C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:4
• 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]

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.*69C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.*184C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494	c.*69C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755	c.*184C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_058195.4	ENSP00000462950.1

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 AC: 4985 AN: 28836

Gnomad4 AMR exome AF: 0.365 AC: 15779 AN: 43222

Gnomad4 ASJ exome AF: 0.0984 AC: 2409 AN: 24470

Gnomad4 EAS exome AF: 0.105 AC: 4034 AN: 38388

Gnomad4 SAS exome AF: 0.159 AC: 12641 AN: 79392

Gnomad4 FIN exome AF: 0.112 AC: 5925 AN: 52702

Gnomad4 NFE exome AF: 0.0861 AC: 77133 AN: 895652

Gnomad4 Remaining exome AF: 0.113 AC: 5917 AN: 52532

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 AC: 0.174815 AN: 0.174815

Gnomad4 AMR AF: 0.253 AC: 0.253146 AN: 0.253146

Gnomad4 ASJ AF: 0.0885 AC: 0.0884726 AN: 0.0884726

Gnomad4 EAS AF: 0.125 AC: 0.12466 AN: 0.12466

Gnomad4 SAS AF: 0.166 AC: 0.165555 AN: 0.165555

Gnomad4 FIN AF: 0.106 AC: 0.106274 AN: 0.106274

Gnomad4 NFE AF: 0.0845 AC: 0.0845317 AN: 0.0845317

Gnomad4 OTH AF: 0.120 AC: 0.120133 AN: 0.120133

Alfa AF: 0.109 Hom.: 453

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

Submissions by phenotype

not specified Benign:2

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.32
DANN	Benign	0.70
Mutation Taster		=100/0	polymorphism (auto)

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;