rs561125706

Variant names:

• chr11-125625878-G-A
• rs561125706
• ENST00000427383.6:c.118G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-125625878-G-A
• chr11-125625878-G-C
• chr11-125625878-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The ENST00000427383.6(CHEK1):​c.118G>A​(p.Gly40Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 702,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CHEK1 ENST00000427383.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.467
• Publications: 0 publications found

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

ENSG00000288907 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03341669).
• BS2: High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK1	NM_001114122.3	c.-155G>A		5_prime_UTR_variant	Exon 1 of 13	ENST00000438015.7	NP_001107594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK1	ENST00000438015.7	c.-155G>A		5_prime_UTR_variant	Exon 1 of 13	5	NM_001114122.3	ENSP00000388648.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152262 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000153 AC: 2 AN: 130390 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000958

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000202

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000127 AC: 7 AN: 550278 Hom.: 0 Cov.: 0 AF XY: 0.00000671 AC XY: 2 AN XY: 297880

African (AFR) AF: 0.0000633 AC: 1 AN: 15806

American (AMR) AF: 0.0000288 AC: 1 AN: 34716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20030

East Asian (EAS) AF: 0.000125 AC: 4 AN: 32104

South Asian (SAS) AF: 0.00 AC: 0 AN: 62776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4076

European-Non Finnish (NFE) AF: 0.00000315 AC: 1 AN: 316978

Other (OTH) AF: 0.00 AC: 0 AN: 30602

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152380 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74510

African (AFR) AF: 0.0000481 AC: 2 AN: 41602

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	3.1
DANN	Benign	0.88
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.87	T
PhyloP100		-0.47
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.16
Sift	Benign	0.83	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.056
MutPred		0.60		Loss of sheet (P = 0.0025);
MVP		0.20
ClinPred		0.034	T
GERP RS		-0.43
PromoterAI		0.036	Neutral
gMVP		0.19
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs561125706; hg19: chr11-125495773;