chr11-125625996-G-A

Variant names:

• chr11-125625996-G-A
• rs556405813
• ENST00000427383.6:c.236G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_001114122.3(CHEK1):​c.-37G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 702,294 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: CHEK1 NM_001114122.3 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.00400
• Publications: 3 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 -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 11-125625996-G-A is Benign according to our data. Variant chr11-125625996-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3035097.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 212 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK1	NM_001114122.3	c.-37G>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.-37G>A		5_prime_UTR_variant	Exon 1 of 13	5	NM_001114122.3	ENSP00000388648.1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00134 AC: 172 AN: 128682 AF XY: 0.00139

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000164

Gnomad ASJ exome AF: 0.000617

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00428

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00202 AC: 1110 AN: 550058 Hom.: 2 Cov.: 0 AF XY: 0.00206 AC XY: 612 AN XY: 297730

African (AFR) AF: 0.000316 AC: 5 AN: 15808

American (AMR) AF: 0.000144 AC: 5 AN: 34714

Ashkenazi Jewish (ASJ) AF: 0.000549 AC: 11 AN: 20030

East Asian (EAS) AF: 0.0000312 AC: 1 AN: 32098

South Asian (SAS) AF: 0.00118 AC: 74 AN: 62770

European-Finnish (FIN) AF: 0.00494 AC: 164 AN: 33180

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4074

European-Non Finnish (NFE) AF: 0.00253 AC: 803 AN: 316790

Other (OTH) AF: 0.00150 AC: 46 AN: 30594

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00151 AC XY: 112 AN XY: 74368

African (AFR) AF: 0.000241 AC: 10 AN: 41466

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00231 AC: 157 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00137 Hom.: 0

Bravo AF: 0.00110

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00120 AC: 20

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CHEK1-related disorder Benign:1

Mar 02, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Benign	0.96
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.028	N
PhyloP100		-0.0040
Vest4		0.17
GERP RS		-1.8
PromoterAI		0.0074	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=46/154	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: -3

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

Other links and lift over

dbSNP: rs556405813; hg19: chr11-125495891; COSMIC: COSV54023927; COSMIC: COSV54023927;