NM_001114122.3:c.1411A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

Publications

53 publications found

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 Gene-Disease associations (from GenCC):

familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CHEK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114122.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHEK1	NM_001114122.3	MANE Select	c.1411A>G	p.Ile471Val	missense	Exon 13 of 13	NP_001107594.1
CHEK1	NM_001114121.2		c.1411A>G	p.Ile471Val	missense	Exon 13 of 14	NP_001107593.1
CHEK1	NM_001274.5		c.1411A>G	p.Ile471Val	missense	Exon 13 of 13	NP_001265.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHEK1	ENST00000438015.7	TSL:5 MANE Select	c.1411A>G	p.Ile471Val	missense	Exon 13 of 13	ENSP00000388648.1
CHEK1	ENST00000427383.6	TSL:1	c.1459A>G	p.Ile487Val	missense	Exon 12 of 12	ENSP00000391090.2
CHEK1	ENST00000428830.6	TSL:1	c.1411A>G	p.Ile471Val	missense	Exon 13 of 14	ENSP00000412504.2

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

GnomAD2 exomes

AF:

0.973

AC:

244403

AN:

251146

AF XY:

0.972

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 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

African (AFR)

AF:

0.995

AC:

33283

AN:

33456

American (AMR)

AF:

0.983

AC:

43943

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.961

AC:

25097

AN:

26122

East Asian (EAS)

AF:

1.00

AC:

39675

AN:

39684

South Asian (SAS)

AF:

0.980

AC:

84492

AN:

86226

European-Finnish (FIN)

AF:

0.967

AC:

51594

AN:

53376

Middle Eastern (MID)

AF:

0.957

AC:

5518

AN:

5764

European-Non Finnish (NFE)

AF:

0.962

AC:

1069170

AN:

1111282

Other (OTH)

AF:

0.968

AC:

58433

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

2163

4326

6489

8652

10815

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21620

43240

64860

86480

108100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.975

AC:

148465

AN:

152312

Hom.:

72370

Cov.:

AF XY:

0.975

AC XY:

72631

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.993

AC:

41291

AN:

41578

American (AMR)

AF:

0.974

AC:

14902

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.956

AC:

3320

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5175

AN:

5176

South Asian (SAS)

AF:

0.978

AC:

4722

AN:

4828

European-Finnish (FIN)

AF:

0.968

AC:

10274

AN:

10612

Middle Eastern (MID)

AF:

0.935

AC:

275

AN:

294

European-Non Finnish (NFE)

AF:

0.964

AC:

65584

AN:

68030

Other (OTH)

AF:

0.963

AC:

2032

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

194

388

581

775

969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.966

Hom.:

241512

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CHEK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.076

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.15

MetaRNN

Benign

6.9e-7

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.2

PhyloP100

1.2

PrimateAI

Benign

0.39

PROVEAN

Benign

0.38

REVEL

Benign

0.053

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

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

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over