rs181044510

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000498124.1(CDKN2A):c.496C>T(p.His166Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000933 in 1,536,164 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 11 hom. )

Consequence

CDKN2A
ENST00000498124.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: -0.385

Variant links:

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]

CDKN2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018141866).

BP6

Variant 9-21968733-G-A is Benign according to our data. Variant chr9-21968733-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133880.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=2, Uncertain_significance=1, Benign=1}.

BS2

High AC in GnomAd4 at 330 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5 linkuse as main transcript	c.458-491C>T		intron_variant		ENST00000304494.10
CDKN2A	NM_058195.4 linkuse as main transcript	c.*102-491C>T		intron_variant		ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10 linkuse as main transcript	c.458-491C>T		intron_variant		1	NM_000077.5	P2	P42771-1
CDKN2A	ENST00000579755.2 linkuse as main transcript	c.*102-491C>T		intron_variant		1	NM_058195.4		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.00216

AC:

329

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00251

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0271

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00138

AC:

186

AN:

134580

Hom.:

AF XY:

0.00124

AC XY:

AN XY:

73302

show subpopulations

Gnomad AFR exome

AF:

0.000156

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00181

Gnomad SAS exome

AF:

0.0000889

Gnomad FIN exome

AF:

0.0271

Gnomad NFE exome

AF:

0.000284

Gnomad OTH exome

AF:

0.000724

GnomAD4 exome

AF:

0.000798

AC:

1104

AN:

1383826

Hom.:

Cov.:

AF XY:

0.000773

AC XY:

528

AN XY:

682858

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.00148

Gnomad4 SAS exome

AF:

0.0000505

Gnomad4 FIN exome

AF:

0.0236

Gnomad4 NFE exome

AF:

0.000165

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00217

AC:

330

AN:

152338

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0271

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000933

Hom.:

Bravo

AF:

0.000317

ExAC

AF:

0.000279

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CDKN2A: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 24728327) -

Melanoma-pancreatic cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Counsyl

Oct 26, 2016

- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.48

CADD

Benign

2.3

DANN

Benign

0.85

Eigen

Benign

-0.85

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.83

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N

PROVEAN

Benign

-0.030

Sift

Benign

0.077

Vest4

0.15

MVP

0.94

MPC

0.45

ClinPred

0.0092

GERP RS

-5.6

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over