11-125625873-C-T

Variant names:

• chr11-125625873-C-T
• rs1940569859
• ENST00000427383.6:c.113C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000427383.6(CHEK1):​c.113C>T​(p.Ser38Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 550,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: CHEK1 ENST00000427383.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.746
• 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: Unknown Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288907 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08032036).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000427383.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK1	NM_001114122.3	MANE Select	c.-160C>T		5_prime_UTR	Exon 1 of 13	NP_001107594.1	O14757-1
	CHEK1	NM_001114121.2		c.-160C>T		5_prime_UTR	Exon 1 of 14	NP_001107593.1	O14757-1
	CHEK1	NM_001244846.1		c.-160C>T		5_prime_UTR	Exon 1 of 12	NP_001231775.1	B4DT73

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK1	ENST00000427383.6	TSL:1	c.113C>T	p.Ser38Leu	missense	Exon 1 of 12	ENSP00000391090.2	E7EPP6
	CHEK1	ENST00000438015.7	TSL:5 MANE Select	c.-160C>T		5_prime_UTR	Exon 1 of 13	ENSP00000388648.1	O14757-1
	CHEK1	ENST00000711049.1		c.113C>T	p.Ser38Leu	missense	Exon 1 of 13	ENSP00000518558.1	E7EPP6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000182 AC: 1 AN: 550278 Hom.: 0 Cov.: 0 AF XY: 0.00000336 AC XY: 1 AN XY: 297878

African (AFR) AF: 0.00 AC: 0 AN: 15808

American (AMR) AF: 0.00 AC: 0 AN: 34716

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

East Asian (EAS) AF: 0.00 AC: 0 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: 316976

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	CHEK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	2.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0080	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.75
PROVEAN	Benign	0.010	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.19
MutPred		0.47		Loss of sheet (P = 0.0037)
MVP		0.37
ClinPred		0.17	T
GERP RS		0.037
PromoterAI		0.12	Neutral
gMVP		0.32
Mutation Taster		=95/5	polymorphism

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: rs1940569859; hg19: chr11-125495768;