Genetic Variant ENST00000427383.6:c.82T>C (chr11-125625842-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.014 ( 29 hom., cov: 33)

Exomes 𝑓: 0.016 ( 85 hom. )

Consequence

CHEK1
ENST00000427383.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

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: Unknown Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: Unknown 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 -14 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 VariationId is 3060002.Status of the report is criteria_provided_single_submitter, 1 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000427383.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHEK1	NM_001114122.3	MANE Select	c.-191T>C	5_prime_UTR	Exon 1 of 13	NP_001107594.1	O14757-1
CHEK1	NM_001114121.2		c.-191T>C	5_prime_UTR	Exon 1 of 14	NP_001107593.1	O14757-1
CHEK1	NM_001244846.1		c.-191T>C	5_prime_UTR	Exon 1 of 12	NP_001231775.1	B4DT73

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHEK1	ENST00000427383.6	TSL:1	c.82T>C	p.Ser28Pro	missense	Exon 1 of 12	ENSP00000391090.2	E7EPP6
CHEK1	ENST00000438015.7	TSL:5 MANE Select	c.-191T>C		5_prime_UTR	Exon 1 of 13	ENSP00000388648.1	O14757-1
CHEK1	ENST00000711049.1		c.82T>C	p.Ser28Pro	missense	Exon 1 of 13	ENSP00000518558.1	E7EPP6

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

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.0140

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

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00783

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

CHEK1-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

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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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