rs200129494

Positions:

• chr9-21974463-AC-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000077.5(CDKN2A):​c.150+214del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,612,006 control chromosomes in the GnomAD database, including 44 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0096 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: CDKN2A NM_000077.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.338

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 -10 ACMG points.

• BP6: Variant 9-21974463-AC-A is Benign according to our data. Variant chr9-21974463-AC-A is described in ClinVar as [Benign]. Clinvar id is 402524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00962 (1466/152326) while in subpopulation AFR AF= 0.0321 (1336/41564). AF 95% confidence interval is 0.0307. There are 21 homozygotes in gnomad4. There are 666 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1466 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.150+214del		intron_variant		ENST00000304494.10
CDKN2A	NM_058195.4	c.194-3256del		intron_variant		ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.150+214del		intron_variant		1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.194-3256del		intron_variant		1	NM_058195.4

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1463 AN: 152208 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00115 AC: 288 AN: 250770 Hom.: 7 AF XY: 0.000781 AC XY: 106 AN XY: 135682

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00112 AC: 1640 AN: 1459680 Hom.: 23 Cov.: 31 AF XY: 0.000964 AC XY: 700 AN XY: 726170

Gnomad4 AFR exome AF: 0.0337

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000937

Gnomad4 FIN exome AF: 0.0000752

Gnomad4 NFE exome AF: 0.000146

Gnomad4 OTH exome AF: 0.00239

GnomAD4 genome AF: 0.00962 AC: 1466 AN: 152326 Hom.: 21 Cov.: 32 AF XY: 0.00894 AC XY: 666 AN XY: 74490

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.000526 Hom.: 0

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

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: rs200129494; hg19: chr9-21974462;