9-21974219-A-G

Position:

• chr9-21974219-A-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.150+459T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,118 control chromosomes in the GnomAD database, including 6,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.26 (6490 hom., cov: 32)
• Consequence: CDKN2A NM_000077.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.922

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=-0.82).
• BP6: Variant 9-21974219-A-G is Benign according to our data. Variant chr9-21974219-A-G is described in ClinVar as [Benign]. Clinvar id is 1241937.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.150+459T>C		intron_variant		ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-3011T>C		intron_variant		ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.150+459T>C		intron_variant		1	NM_000077.5	ENSP00000307101	P2
CDKN2A	ENST00000579755.2	c.194-3011T>C		intron_variant		1	NM_058195.4	ENSP00000462950

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38995 AN: 152000 Hom.: 6492 Cov.: 32

Gnomad AFR AF: 0.0648

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.245

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.256 AC: 38988 AN: 152118 Hom.: 6490 Cov.: 32 AF XY: 0.257 AC XY: 19070 AN XY: 74336

Gnomad4 AFR AF: 0.0646

Gnomad4 AMR AF: 0.212

Gnomad4 ASJ AF: 0.264

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.421

Gnomad4 NFE AF: 0.371

Gnomad4 OTH AF: 0.246

Alfa AF: 0.337 Hom.: 13530

Bravo AF: 0.233

Asia WGS AF: 0.196 AC: 683 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.7
DANN	Benign	0.25

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: rs3731239; hg19: chr9-21974218; COSMIC: COSV58718323; COSMIC: COSV58718323;