11-125655300-A-G

Position:

• chr11-125655300-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001114122.3(CHEK1):​c.1411A>G​(p.Ile471Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 1,613,302 control chromosomes in the GnomAD database, including 754,123 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.97 (72370 hom., cov: 31)
  • Exomes 𝑓: 0.97 (681753 hom.)
• Consequence: CHEK1 NM_001114122.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.21

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.8550537E-7).
• BP6: Variant 11-125655300-A-G is Benign according to our data. Variant chr11-125655300-A-G is described in ClinVar as [Benign]. Clinvar id is 496139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK1	NM_001114122.3	c.1411A>G	p.Ile471Val	missense_variant	13/13	ENST00000438015.7	NP_001107594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK1	ENST00000438015.7	c.1411A>G	p.Ile471Val	missense_variant	13/13	5	NM_001114122.3	ENSP00000388648	P1

Frequencies

GnomAD3 genomes AF: 0.975 AC: 148344 AN: 152194 Hom.: 72309 Cov.: 31

Gnomad AFR AF: 0.993

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.974

Gnomad ASJ AF: 0.956

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.978

Gnomad FIN AF: 0.968

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.964

Gnomad OTH AF: 0.963

GnomAD3 exomes AF: 0.973 AC: 244403 AN: 251146 Hom.: 118967 AF XY: 0.972 AC XY: 131977 AN XY: 135762

Gnomad AFR exome AF: 0.995

Gnomad AMR exome AF: 0.984

Gnomad ASJ exome AF: 0.965

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.980

Gnomad FIN exome AF: 0.967

Gnomad NFE exome AF: 0.963

Gnomad OTH exome AF: 0.969

GnomAD4 exome AF: 0.966 AC: 1411205 AN: 1460990 Hom.: 681753 Cov.: 37 AF XY: 0.966 AC XY: 702062 AN XY: 726824

Gnomad4 AFR exome AF: 0.995

Gnomad4 AMR exome AF: 0.983

Gnomad4 ASJ exome AF: 0.961

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.980

Gnomad4 FIN exome AF: 0.967

Gnomad4 NFE exome AF: 0.962

Gnomad4 OTH exome AF: 0.968

GnomAD4 genome AF: 0.975 AC: 148465 AN: 152312 Hom.: 72370 Cov.: 31 AF XY: 0.975 AC XY: 72631 AN XY: 74472

Gnomad4 AFR AF: 0.993

Gnomad4 AMR AF: 0.974

Gnomad4 ASJ AF: 0.956

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.978

Gnomad4 FIN AF: 0.968

Gnomad4 NFE AF: 0.964

Gnomad4 OTH AF: 0.963

Alfa AF: 0.965 Hom.: 172098

Bravo AF: 0.975

TwinsUK AF: 0.958 AC: 3551

ALSPAC AF: 0.959 AC: 3695

ESP6500AA AF: 0.994 AC: 4374

ESP6500EA AF: 0.964 AC: 8286

ExAC AF: 0.973 AC: 118071

Asia WGS AF: 0.992 AC: 3449 AN: 3478

EpiCase AF: 0.962

EpiControl AF: 0.958

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 03, 2016	- -

CHEK1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 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
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.53
DEOGEN2	Benign	0.076	.;T;T;T;.;T;T;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.15	T;T;T;.;T;.;.;T
MetaRNN	Benign	6.9e-7	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.2	.;N;.;N;.;N;N;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.38	.;N;N;N;.;N;N;N
REVEL	Benign	0.053
Sift	Benign	1.0	.;T;T;T;.;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;B;B;.;B;B;.
Vest4		0.057
MPC		0.34
ClinPred		0.0040	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.013
gMVP		0.043

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: rs506504; hg19: chr11-125525195;