Genetic Variant CHEK1:p.Ser28Pro (chr11-125625842-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000427383.6(CHEK1):c.82T>C(p.Ser28Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 702,552 control chromosomes in the GnomAD database, including 114 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 0.014 ( 29 hom., cov: 33)

Exomes 𝑓: 0.016 ( 85 hom. )

Consequence

CHEK1
ENST00000427383.6 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -3.12

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=0.0037466586).

BP6

Variant 11-125625842-T-C is Benign according to our data. Variant chr11-125625842-T-C is described in ClinVar as [Benign]. Clinvar id is 3060002.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.014 (2126/152314) while in subpopulation NFE AF= 0.0219 (1488/68022). AF 95% confidence interval is 0.021. There are 29 homozygotes in gnomad4. There are 957 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2126 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK1	NM_001114122.3 link	c.-191T>C		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.-191T>C		5_prime_UTR_variant	Exon 1 of 13	5	NM_001114122.3	ENSP00000388648.1		O14757-1

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2128

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00396

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.00955

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0112

Gnomad FIN

AF:

0.0166

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0219

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0130

AC:

1704

AN:

130688

Hom.:

AF XY:

0.0136

AC XY:

973

AN XY:

71356

show subpopulations

Gnomad AFR exome

AF:

0.00394

Gnomad AMR exome

AF:

0.00530

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0111

Gnomad FIN exome

AF:

0.0188

Gnomad NFE exome

AF:

0.0211

Gnomad OTH exome

AF:

0.0110

GnomAD4 exome

AF:

0.0164

AC:

9037

AN:

550238

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

4849

AN XY:

297862

show subpopulations

Gnomad4 AFR exome

AF:

0.00392

Gnomad4 AMR exome

AF:

0.00579

Gnomad4 ASJ exome

AF:

0.0124

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0112

Gnomad4 FIN exome

AF:

0.0187

Gnomad4 NFE exome

AF:

0.0213

Gnomad4 OTH exome

AF:

0.0143

GnomAD4 genome

AF:

0.0140

AC:

2126

AN:

152314

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

957

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00394

Gnomad4 AMR

AF:

0.00954

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0110

Gnomad4 FIN

AF:

0.0166

Gnomad4 NFE

AF:

0.0219

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00783

Hom.:

Bravo

AF:

0.0127

TwinsUK

AF:

0.0275

AC:

102

ALSPAC

AF:

0.0285

AC:

110

ExAC

AF:

0.00839

AC:

134

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CHEK1-related disorder

Benign:1

Nov 15, 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

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.80

DANN

Benign

0.75

DEOGEN2

Benign

0.0077

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0037

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.89

REVEL

Benign

0.050

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.19

Vest4

0.19

ClinPred

0.030

GERP RS

-2.6

gMVP

0.19

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