11-125625851-C-G

Variant names:

• chr11-125625851-C-G
• rs76045215
• ENST00000427383.6:c.91C>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.-182C>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 702,562 control chromosomes in the GnomAD database, including 3,088 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 (1468 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: -3.79
• Publications: 14 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=0.00483346).
• BP6: Variant 11-125625851-C-G is Benign according to our data. Variant chr11-125625851-C-G is described in ClinVar as [Benign]. Clinvar id is 3055541.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.-182C>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.-182C>G		5_prime_UTR_variant	Exon 1 of 13	5	NM_001114122.3	ENSP00000388648.1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17100 AN: 152202 Hom.: 1465 Cov.: 33

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.0667

Gnomad ASJ AF: 0.0783

Gnomad EAS AF: 0.0216

Gnomad SAS AF: 0.0550

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0659

Gnomad OTH AF: 0.112

GnomAD2 exomes AF: 0.0657 AC: 8588 AN: 130658 AF XY: 0.0641

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.0453

Gnomad ASJ exome AF: 0.0773

Gnomad EAS exome AF: 0.0267

Gnomad FIN exome AF: 0.0476

Gnomad NFE exome AF: 0.0681

Gnomad OTH exome AF: 0.0859

GnomAD4 exome AF: 0.0663 AC: 36470 AN: 550242 Hom.: 1620 Cov.: 0 AF XY: 0.0639 AC XY: 19036 AN XY: 297860

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: 1577 AN: 20028

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

South Asian (SAS) AF: 0.0490 AC: 3076 AN: 62772

European-Finnish (FIN) AF: 0.0491 AC: 1628 AN: 33188

Middle Eastern (MID) AF: 0.129 AC: 523 AN: 4070

European-Non Finnish (NFE) AF: 0.0661 AC: 20958 AN: 316958

Other (OTH) AF: 0.0832 AC: 2545 AN: 30600

GnomAD4 genome AF: 0.112 AC: 17131 AN: 152320 Hom.: 1468 Cov.: 33 AF XY: 0.109 AC XY: 8146 AN XY: 74486

African (AFR) AF: 0.242 AC: 10037 AN: 41556

American (AMR) AF: 0.0666 AC: 1019 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0783 AC: 272 AN: 3472

East Asian (EAS) AF: 0.0218 AC: 113 AN: 5180

South Asian (SAS) AF: 0.0548 AC: 265 AN: 4832

European-Finnish (FIN) AF: 0.0439 AC: 467 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0659 AC: 4484 AN: 68028

Other (OTH) AF: 0.110 AC: 232 AN: 2114

Alfa AF: 0.0503 Hom.: 67

Bravo AF: 0.120

TwinsUK AF: 0.0709 AC: 263

ALSPAC AF: 0.0620 AC: 239

ExAC AF: 0.0452 AC: 718

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	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.19
DANN	Benign	0.45
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
PhyloP100		-3.8
PROVEAN	Benign	0.25	N
REVEL	Benign	0.049
Sift	Benign	0.19	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.031
ClinPred		0.0032	T
GERP RS		-3.3
PromoterAI		-0.094	Neutral
gMVP		0.12
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76045215; hg19: chr11-125495746; COSMIC: COSV54022102; COSMIC: COSV54022102;