11-125625842-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001114122.3(CHEK1):c.-191T>C variant causes a 5 prime UTR 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. 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
NM_001114122.3 5_prime_UTR

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -3.12

Publications

7 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:

ENSG00000288907 (HGNC:):

ENSG00000288907 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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	ENST00000438015.7 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

GnomAD2 exomes

AF:

0.0130

AC:

1704

AN:

130688

AF XY:

0.0136

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 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

African (AFR)

AF:

0.00392

AC:

AN:

15808

American (AMR)

AF:

0.00579

AC:

201

AN:

34716

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

249

AN:

20028

East Asian (EAS)

AF:

0.00

AC:

AN:

32092

South Asian (SAS)

AF:

0.0112

AC:

705

AN:

62772

European-Finnish (FIN)

AF:

0.0187

AC:

620

AN:

33186

Middle Eastern (MID)

AF:

0.00319

AC:

AN:

4076

European-Non Finnish (NFE)

AF:

0.0213

AC:

6749

AN:

316958

Other (OTH)

AF:

0.0143

AC:

438

AN:

30602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

572

1145

1717

2290

2862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0140

AC:

2126

AN:

152314

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

957

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00394

AC:

164

AN:

41582

American (AMR)

AF:

0.00954

AC:

146

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.0110

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0166

AC:

176

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0219

AC:

1488

AN:

68022

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

115

230

346

461

576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

(source)

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

PhyloP100

-3.1

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

PromoterAI

-0.0085

Neutral

(source)

gMVP

0.19

Mutation Taster

=98/2

polymorphism

(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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11-125625842-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over