11-125655300-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001114122.3(CHEK1):c.1411A>G(p.Ile471Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 1,613,302 control chromosomes in the GnomAD database, including 754,123 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.97 ( 72370 hom., cov: 31)

Exomes 𝑓: 0.97 ( 681753 hom. )

Consequence

CHEK1
NM_001114122.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.21

Variant links:

Genes affected

CHEK1 (HGNC:1925): (checkpoint kinase 1) The protein encoded by this gene belongs to the Ser/Thr protein kinase family. It is required for checkpoint mediated cell cycle arrest in response to DNA damage or the presence of unreplicated DNA. This protein acts to integrate signals from ATM and ATR, two cell cycle proteins involved in DNA damage responses, that also associate with chromatin in meiotic prophase I. Phosphorylation of CDC25A protein phosphatase by this protein is required for cells to delay cell cycle progression in response to double-strand DNA breaks. Several alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Oct 2011]

CHEK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.8550537E-7).

BP6

Variant 11-125655300-A-G is Benign according to our data. Variant chr11-125655300-A-G is described in ClinVar as [Benign]. Clinvar id is 496139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK1	NM_001114122.3 link	c.1411A>G	p.Ile471Val	missense_variant	Exon 13 of 13	ENST00000438015.7	NP_001107594.1	O14757-1B4DT73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK1	ENST00000438015.7 link	c.1411A>G	p.Ile471Val	missense_variant	Exon 13 of 13	5	NM_001114122.3	ENSP00000388648.1		O14757-1

Frequencies

GnomAD3 genomes

AF:

0.975

AC:

148344

AN:

152194

Hom.:

72309

Cov.:

show subpopulations

Gnomad AFR

AF:

0.993

Gnomad AMI

AF:

0.976

Gnomad AMR

AF:

0.974

Gnomad ASJ

AF:

0.956

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.978

Gnomad FIN

AF:

0.968

Gnomad MID

AF:

0.937

Gnomad NFE

AF:

0.964

Gnomad OTH

AF:

0.963

GnomAD3 exomes

AF:

0.973

AC:

244403

AN:

251146

Hom.:

118967

AF XY:

0.972

AC XY:

131977

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.995

Gnomad AMR exome

AF:

0.984

Gnomad ASJ exome

AF:

0.965

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.980

Gnomad FIN exome

AF:

0.967

Gnomad NFE exome

AF:

0.963

Gnomad OTH exome

AF:

0.969

GnomAD4 exome

AF:

0.966

AC:

1411205

AN:

1460990

Hom.:

681753

Cov.:

AF XY:

0.966

AC XY:

702062

AN XY:

726824

show subpopulations

Gnomad4 AFR exome

AF:

0.995

Gnomad4 AMR exome

AF:

0.983

Gnomad4 ASJ exome

AF:

0.961

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.980

Gnomad4 FIN exome

AF:

0.967

Gnomad4 NFE exome

AF:

0.962

Gnomad4 OTH exome

AF:

0.968

GnomAD4 genome

AF:

0.975

AC:

148465

AN:

152312

Hom.:

72370

Cov.:

AF XY:

0.975

AC XY:

72631

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.993

Gnomad4 AMR

AF:

0.974

Gnomad4 ASJ

AF:

0.956

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.978

Gnomad4 FIN

AF:

0.968

Gnomad4 NFE

AF:

0.964

Gnomad4 OTH

AF:

0.963

Alfa

AF:

0.965

Hom.:

172098

Bravo

AF:

0.975

TwinsUK

AF:

0.958

AC:

3551

ALSPAC

AF:

0.959

AC:

3695

ESP6500AA

AF:

0.994

AC:

4374

ESP6500EA

AF:

0.964

AC:

8286

ExAC

AF:

0.973

AC:

118071

Asia WGS

AF:

0.992

AC:

3449

AN:

3478

EpiCase

AF:

0.962

EpiControl

AF:

0.958

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CHEK1-related disorder

Benign:1

Nov 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.53

DEOGEN2

Benign

0.076

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

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.15

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

MetaRNN

Benign

6.9e-7

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

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.2

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

PrimateAI

Benign

0.39

PROVEAN

Benign

0.38

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

REVEL

Benign

0.053

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

.;B;B;B;.;B;B;.

Vest4

0.057

MPC

0.34

ClinPred

0.0040

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.013

gMVP

0.043

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