chr6-36684352-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000389.5(CDKN1A):c.251G>A(p.Arg84Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,613,402 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 24 hom. )

Consequence

CDKN1A
NM_000389.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.663

Variant links:

Genes affected

CDKN1A (HGNC:1784): (cyclin dependent kinase inhibitor 1A) This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-cyclin-dependent kinase2 or -cyclin-dependent kinase4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This protein can interact with proliferating cell nuclear antigen, a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of cyclin-dependent kinase2, and may be instrumental in the execution of apoptosis following caspase activation. Mice that lack this gene have the ability to regenerate damaged or missing tissue. Multiple alternatively spliced variants have been found for this gene. [provided by RefSeq, Sep 2015]

CDKN1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005693376).

BP6

Variant 6-36684352-G-A is Benign according to our data. Variant chr6-36684352-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 790317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-36684352-G-A is described in Lovd as [Likely_benign]. Variant chr6-36684352-G-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 357 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1A	NM_000389.5 link	c.251G>A	p.Arg84Gln	missense_variant	Exon 2 of 3	ENST00000244741.10	NP_000380.1	P38936A0A024RCX5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1A	ENST00000244741.10 link	c.251G>A	p.Arg84Gln	missense_variant	Exon 2 of 3	1	NM_000389.5	ENSP00000244741.6		P38936

Frequencies

GnomAD3 genomes

AF:

0.00232

AC:

353

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00395

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00246

AC:

611

AN:

248472

Hom.:

AF XY:

0.00250

AC XY:

337

AN XY:

134640

show subpopulations

Gnomad AFR exome

AF:

0.000882

Gnomad AMR exome

AF:

0.00128

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00203

Gnomad FIN exome

AF:

0.00191

Gnomad NFE exome

AF:

0.00385

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.00360

AC:

5256

AN:

1461100

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

2559

AN XY:

726820

show subpopulations

Gnomad4 AFR exome

AF:

0.000628

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00195

Gnomad4 FIN exome

AF:

0.00153

Gnomad4 NFE exome

AF:

0.00423

Gnomad4 OTH exome

AF:

0.00346

GnomAD4 genome

AF:

0.00234

AC:

357

AN:

152302

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

162

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00396

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00263

Hom.:

Bravo

AF:

0.00220

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00274

AC:

333

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00338

EpiControl

AF:

0.00332

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDKN1A: BP4, BS2 -

Jan 12, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

8.3

DANN

Benign

0.85

DEOGEN2

Benign

0.023

T;T;T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.64

.;T;.;.;.

M_CAP

Benign

0.013

MetaRNN

Benign

0.0057

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.17

.;.;N;N;N

REVEL

Benign

0.036

Sift

Benign

0.38

.;.;T;T;T

Sift4G

Benign

0.45

T;T;T;T;T

Polyphen

0.24

B;B;B;B;B

Vest4

0.14

MVP

0.62

MPC

0.20

ClinPred

0.0025

GERP RS

2.5

Varity_R

0.064

gMVP

0.37

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

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