11-125625842-T-C

Position:

• chr11-125625842-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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 (★).

• Frequency:
  • Genomes: 𝑓 0.014 (29 hom., cov: 33)
  • Exomes 𝑓: 0.016 (85 hom.)
• Consequence: CHEK1 ENST00000427383.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.12

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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 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/exons	MANE	UniProt
CHEK1	NM_001114122.3	c.-191T>C		5_prime_UTR_variant	1/13	ENST00000438015.7
LOC118567325	NR_170378.1	n.53A>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK1	ENST00000438015.7	c.-191T>C		5_prime_UTR_variant	1/13	5	NM_001114122.3	P1
	ENST00000686400.2	n.72A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2128 AN: 152196 Hom.: 29 Cov.: 33

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.: 10 AF XY: 0.0136 AC XY: 973 AN XY: 71356

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.: 85 Cov.: 0 AF XY: 0.0163 AC XY: 4849 AN XY: 297862

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.: 29 Cov.: 33 AF XY: 0.0128 AC XY: 957 AN XY: 74480

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.: 2

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: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CHEK1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 15, 2019

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	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.80
DANN	Benign	0.75
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.050
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.19	B
Vest4		0.19
ClinPred		0.030	T
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

Other links and lift over

dbSNP: rs112362212; hg19: chr11-125495737; COSMIC: COSV54025086; COSMIC: COSV54025086;