rs537046

Variant names:

• chr11-125639943-A-G
• rs537046
• NM_001114122.3:c.814+2399A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001114122.3(CHEK1):​c.814+2399A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 151,954 control chromosomes in the GnomAD database, including 1,333 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1333 hom., cov: 32)
• Consequence: CHEK1 NM_001114122.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.256
• Publications: 9 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK1	NM_001114122.3	c.814+2399A>G		intron_variant	Intron 8 of 12	ENST00000438015.7	NP_001107594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK1	ENST00000438015.7	c.814+2399A>G		intron_variant	Intron 8 of 12	5	NM_001114122.3	ENSP00000388648.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19184 AN: 151836 Hom.: 1334 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0878

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.0872

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.125

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.126 AC: 19188 AN: 151954 Hom.: 1333 Cov.: 32 AF XY: 0.125 AC XY: 9315 AN XY: 74252

African (AFR) AF: 0.102 AC: 4220 AN: 41440

American (AMR) AF: 0.0875 AC: 1335 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 550 AN: 3464

East Asian (EAS) AF: 0.204 AC: 1056 AN: 5166

South Asian (SAS) AF: 0.174 AC: 834 AN: 4800

European-Finnish (FIN) AF: 0.0872 AC: 920 AN: 10556

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.145 AC: 9877 AN: 67952

Other (OTH) AF: 0.128 AC: 270 AN: 2112

Alfa AF: 0.135 Hom.: 523

Bravo AF: 0.124

Asia WGS AF: 0.156 AC: 544 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.2
DANN	Benign	0.40
PhyloP100		-0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs537046; hg19: chr11-125509838;