11-125625845-A-G

Variant names:

• chr11-125625845-A-G
• rs77183579
• ENST00000427383.6:c.85A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001114122.3(CHEK1):​c.-188A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0763 in 702,408 control chromosomes in the GnomAD database, including 3,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.11 (1467 hom., cov: 33)
  • Exomes 𝑓: 0.066 (1620 hom.)
• Consequence: CHEK1 NM_001114122.3 5_prime_UTR
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -4.09
• Publications: 15 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052491426).
• BP6: Variant 11-125625845-A-G is Benign according to our data. Variant chr11-125625845-A-G is described in ClinVar as [Benign]. Clinvar id is 3056356.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK1	NM_001114122.3	c.-188A>G		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.-188A>G		5_prime_UTR_variant	Exon 1 of 13	5	NM_001114122.3	ENSP00000388648.1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17099 AN: 152064 Hom.: 1464 Cov.: 33

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.0667

Gnomad ASJ AF: 0.0784

Gnomad EAS AF: 0.0217

Gnomad SAS AF: 0.0551

Gnomad FIN AF: 0.0440

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0660

Gnomad OTH AF: 0.112

GnomAD2 exomes AF: 0.0658 AC: 8597 AN: 130688 AF XY: 0.0641

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.0453

Gnomad ASJ exome AF: 0.0774

Gnomad EAS exome AF: 0.0267

Gnomad FIN exome AF: 0.0476

Gnomad NFE exome AF: 0.0682

Gnomad OTH exome AF: 0.0859

GnomAD4 exome AF: 0.0663 AC: 36476 AN: 550226 Hom.: 1620 Cov.: 0 AF XY: 0.0639 AC XY: 19038 AN XY: 297854

African (AFR) AF: 0.245 AC: 3871 AN: 15806

American (AMR) AF: 0.0492 AC: 1707 AN: 34716

Ashkenazi Jewish (ASJ) AF: 0.0787 AC: 1576 AN: 20026

East Asian (EAS) AF: 0.0182 AC: 585 AN: 32104

South Asian (SAS) AF: 0.0490 AC: 3077 AN: 62772

European-Finnish (FIN) AF: 0.0491 AC: 1628 AN: 33186

Middle Eastern (MID) AF: 0.128 AC: 522 AN: 4070

European-Non Finnish (NFE) AF: 0.0661 AC: 20965 AN: 316948

Other (OTH) AF: 0.0832 AC: 2545 AN: 30598

GnomAD4 genome AF: 0.113 AC: 17130 AN: 152182 Hom.: 1467 Cov.: 33 AF XY: 0.109 AC XY: 8144 AN XY: 74412

African (AFR) AF: 0.242 AC: 10032 AN: 41518

American (AMR) AF: 0.0666 AC: 1019 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0784 AC: 272 AN: 3470

East Asian (EAS) AF: 0.0219 AC: 113 AN: 5160

South Asian (SAS) AF: 0.0549 AC: 265 AN: 4826

European-Finnish (FIN) AF: 0.0440 AC: 467 AN: 10604

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0660 AC: 4488 AN: 67984

Other (OTH) AF: 0.110 AC: 232 AN: 2112

Alfa AF: 0.0846 Hom.: 209

Bravo AF: 0.120

TwinsUK AF: 0.0709 AC: 263

ALSPAC AF: 0.0625 AC: 241

ExAC AF: 0.0456 AC: 719

Asia WGS AF: 0.0620 AC: 216 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CHEK1-related disorder Benign:1

Oct 30, 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	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.040
DANN	Benign	0.29
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.1	T
PhyloP100		-4.1
PROVEAN	Benign	0.45	N
REVEL	Benign	0.078
Sift	Benign	1.0	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.027
ClinPred		0.0034	T
GERP RS		-1.4
PromoterAI		-0.16	Neutral
gMVP		0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs77183579; hg19: chr11-125495740; COSMIC: COSV54022096; COSMIC: COSV54022096;