chr9-21970917-C-T

Position:

chr9-21970917-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000304494.10(CDKN2A):c.442G>A(p.Ala148Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0244 in 1,612,214 control chromosomes in the GnomAD database, including 600 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A148P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.020 ( 45 hom., cov: 32)

Exomes 𝑓: 0.025 ( 555 hom. )

Consequence

CDKN2A
ENST00000304494.10 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:21O:1

Conservation

PhyloP100: 0.153

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 -18 ACMG points.

PM1

In a chain Cyclin-dependent kinase inhibitor 2A (size 155) in uniprot entity CDN2A_HUMAN there are 120 pathogenic changes around while only 33 benign (78%) in ENST00000304494.10

BP4

Computational evidence support a benign effect (MetaRNN=0.0030647516).

BP6

Variant 9-21970917-C-T is Benign according to our data. Variant chr9-21970917-C-T is described in ClinVar as [Benign]. Clinvar id is 41580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21970917-C-T is described in Lovd as [Benign]. Variant chr9-21970917-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0197 (2999/152342) while in subpopulation NFE AF= 0.031 (2105/68010). AF 95% confidence interval is 0.0298. There are 45 homozygotes in gnomad4. There are 1452 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2999 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5 linkuse as main transcript	c.442G>A	p.Ala148Thr	missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4 linkuse as main transcript	c.*86G>A		3_prime_UTR_variant	2/3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10 linkuse as main transcript	c.442G>A	p.Ala148Thr	missense_variant	2/3	1	NM_000077.5	ENSP00000307101	P2	P42771-1
CDKN2A	ENST00000579755.2 linkuse as main transcript	c.*86G>A		3_prime_UTR_variant	2/3	1	NM_058195.4	ENSP00000462950		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.0197

AC:

2999

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00492

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0258

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00744

Gnomad FIN

AF:

0.00508

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0309

Gnomad OTH

AF:

0.0201

GnomAD3 exomes

AF:

0.0209

AC:

5159

AN:

246916

Hom.:

AF XY:

0.0219

AC XY:

2935

AN XY:

134074

show subpopulations

Gnomad AFR exome

AF:

0.00360

Gnomad AMR exome

AF:

0.0158

Gnomad ASJ exome

AF:

0.0302

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0100

Gnomad FIN exome

AF:

0.00548

Gnomad NFE exome

AF:

0.0332

Gnomad OTH exome

AF:

0.0259

GnomAD4 exome

AF:

0.0249

AC:

36385

AN:

1459872

Hom.:

555

Cov.:

AF XY:

0.0249

AC XY:

18099

AN XY:

726302

show subpopulations

Gnomad4 AFR exome

AF:

0.00448

Gnomad4 AMR exome

AF:

0.0166

Gnomad4 ASJ exome

AF:

0.0291

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0105

Gnomad4 FIN exome

AF:

0.00708

Gnomad4 NFE exome

AF:

0.0287

Gnomad4 OTH exome

AF:

0.0236

GnomAD4 genome

AF:

0.0197

AC:

2999

AN:

152342

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

1452

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00490

Gnomad4 AMR

AF:

0.0258

Gnomad4 ASJ

AF:

0.0311

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00765

Gnomad4 FIN

AF:

0.00508

Gnomad4 NFE

AF:

0.0310

Gnomad4 OTH

AF:

0.0199

Alfa

AF:

0.0294

Hom.:

181

Bravo

AF:

0.0199

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0293

AC:

113

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0321

AC:

276

ExAC

AF:

0.0224

AC:

2717

Asia WGS

AF:

0.00462

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:21Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2012	- -
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:4

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 25, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 20, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -

Melanoma-pancreatic cancer syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 20, 2023	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Familial melanoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

T;.;.;.;.;T;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.77

T;.;T;.;T;T;T

MetaRNN

Benign

0.0031

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.86

N;.;N;.;.;.;.

REVEL

Benign

0.27

Sift

Uncertain

0.0030

D;.;D;.;.;.;.

Sift4G

Uncertain

0.041

D;T;D;T;T;D;D

Polyphen

0.49

P;.;.;.;.;.;.

Vest4

0.092

MPC

0.39

ClinPred

0.012

GERP RS

1.1

Varity_R

0.096

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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