CHEK1

protein-coding

checkpoint kinase 1

Gene summary

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]

MANE transcript

NM_001114122.3

Inheritance

ClinVar variants

P:5U:47B:32

Top phenotype

Oocyte/zygote/embryo maturation arrest 21

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr11:125,625,163-125,676,255

External References & Databases

Ensembl (ENSG00000149554)

Transcript & Mutation Effects

hg38 • Region Span ~51.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary breast carcinomaNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0016419

Submitter: ClinGen

familial ovarian cancerNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0016248

Submitter: ClinGen

Clinical Genomic Database (CGD)

Oocyte/zygote/embryo maturation arrest 21AD

Manifestation: Obstetric

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 33948904; 33953335; 35231158

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHEK1 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 58

CHEK1-related disorderTotal: 17

Oocyte/zygote/embryo maturation arrest 21Total: 7

not providedTotal: 6

Hereditary cancer-predisposing syndromeTotal: 6

Male infertility due to gonadal dysgenesis or sperm disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001114122.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	27 clinvar	1 clinvar	29
missense	3 clinvar		42 clinvar	3 clinvar		48
nonsense		1 clinvar	1 clinvar			2
start loss						0
frameshift	1 clinvar		1 clinvar	1 clinvar		3
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	4	1	47	31	1	84

Highest pathogenic variant AF is 0.00005885793

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001114122.3	RefSeq	NP_001107594.1	12	MANE Select
ENST00000438015.7	Ensembl	ENSP00000388648.1	12	MANE Select
NM_001114121.2	RefSeq	NP_001107593.1	12	Standard
NM_001244846.1	RefSeq	NP_001231775.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
chek1	Danio rerio	Structure: swim bladder Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

chek1

Danio rerio

Structure: swim bladder

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell cycle - Homo sapiens (human)
p53 signaling pathway - Homo sapiens (human)
HTLV-I infection - Homo sapiens (human)
Viral carcinogenesis - Homo sapiens (human)
Cellular senescence - Homo sapiens (human)

Biological Process

DNA damage checkpoint
DNA replication
DNA repair
protein phosphorylation
apoptotic process

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
protein binding
ATP binding
kinase activity

Cellular Component

chromosome, telomeric region
chromatin
condensed nuclear chromosome
extracellular space
nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000534070
Coding exons: 12
Length: 51115
Individuals with no LoFs: 125707
Homozygous LoFs: 0
Heterozygous LoFs: 41
Defined: 125748
p: 0.000163

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.78	170	249	0.683	0.0000121	3143
Missense (PolyPhen)		53	107.08	0.49498		1338
Synonymous	-0.477	89	83.5	1.07	0.00000382	852
Loss of Function	1.83	16	26.1	0.613	0.00000129	337

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00020	0.00020	rare
South Asian	0.00020	0.00016	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser- 124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell- cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest.;

Recessive Scores

pRec: 0.527

Intolerance Scores

LoFtool: 0.961
RVIS EVS: -0.32
RVIS percentile EVS: 31.69

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.830

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium