Genetic Variant ENST00000427383.6:c.85A>G (chr11-125625845-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000427383.6(CHEK1):c.85A>G(p.Thr29Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0763 in 702,408 control chromosomes in the GnomAD database, including 3,087 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.11 ( 1467 hom., cov: 33)

Exomes 𝑓: 0.066 ( 1620 hom. )

Consequence

CHEK1
ENST00000427383.6 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -4.09

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:

ENSG00000288907 (HGNC:):

ENSG00000288907 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052491426).

BP6

Variant 11-125625845-A-G is Benign according to our data. Variant chr11-125625845-A-G is described in ClinVar as [Benign]. Clinvar id is 3056356.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK1	NM_001114122.3 link	c.-188A>G		5_prime_UTR_variant	Exon 1 of 13	ENST00000438015.7	NP_001107594.1	O14757-1B4DT73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK1	ENST00000438015 link	c.-188A>G		5_prime_UTR_variant	Exon 1 of 13	5	NM_001114122.3	ENSP00000388648.1		O14757-1

Frequencies

GnomAD3 genomes

AF:

0.112

AC:

17099

AN:

152064

Hom.:

1464

Cov.:

show subpopulations

Gnomad AFR

AF:

0.241

Gnomad AMI

AF:

0.233

Gnomad AMR

AF:

0.0667

Gnomad ASJ

AF:

0.0784

Gnomad EAS

AF:

0.0217

Gnomad SAS

AF:

0.0551

Gnomad FIN

AF:

0.0440

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0660

Gnomad OTH

AF:

0.112

GnomAD3 exomes

AF:

0.0658

AC:

8597

AN:

130688

Hom.:

416

AF XY:

0.0641

AC XY:

4574

AN XY:

71352

show subpopulations

Gnomad AFR exome

AF:

0.244

Gnomad AMR exome

AF:

0.0453

Gnomad ASJ exome

AF:

0.0774

Gnomad EAS exome

AF:

0.0267

Gnomad SAS exome

AF:

0.0491

Gnomad FIN exome

AF:

0.0476

Gnomad NFE exome

AF:

0.0682

Gnomad OTH exome

AF:

0.0859

GnomAD4 exome

AF:

0.0663

AC:

36476

AN:

550226

Hom.:

1620

Cov.:

AF XY:

0.0639

AC XY:

19038

AN XY:

297854

show subpopulations

Gnomad4 AFR exome

AF:

0.245

Gnomad4 AMR exome

AF:

0.0492

Gnomad4 ASJ exome

AF:

0.0787

Gnomad4 EAS exome

AF:

0.0182

Gnomad4 SAS exome

AF:

0.0490

Gnomad4 FIN exome

AF:

0.0491

Gnomad4 NFE exome

AF:

0.0661

Gnomad4 OTH exome

AF:

0.0832

GnomAD4 genome

AF:

0.113

AC:

17130

AN:

152182

Hom.:

1467

Cov.:

AF XY:

0.109

AC XY:

8144

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.242

Gnomad4 AMR

AF:

0.0666

Gnomad4 ASJ

AF:

0.0784

Gnomad4 EAS

AF:

0.0219

Gnomad4 SAS

AF:

0.0549

Gnomad4 FIN

AF:

0.0440

Gnomad4 NFE

AF:

0.0660

Gnomad4 OTH

AF:

0.110

Alfa

AF:

0.0815

Hom.:

190

Bravo

AF:

0.120

TwinsUK

AF:

0.0709

AC:

263

ALSPAC

AF:

0.0625

AC:

241

ExAC

AF:

0.0456

AC:

719

Asia WGS

AF:

0.0620

AC:

216

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CHEK1-related disorder

Benign:1

Oct 30, 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

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.040

DANN

Benign

0.29

DEOGEN2

Benign

0.0051

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0019

LIST_S2

Benign

0.17

MetaRNN

Benign

0.0052

MetaSVM

Benign

-1.1

PROVEAN

Benign

0.45

REVEL

Benign

0.078

Sift

Benign

1.0

Sift4G

Benign

0.93

Polyphen

0.0

Vest4

0.027

ClinPred

0.0034

GERP RS

-1.4

gMVP

0.14

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