CLOCK
clock circadian regulator, the group of Lysine acetyltransferases|Basic helix-loop-helix proteins|PAS domain containing
Basic information
Region (hg38): 4:55427902-55546909
Links
Phenotypes
GenCC
Source:
No genCC data.
ClinVar
This is a list of variants' phenotypes submitted to
- Inborn genetic diseases (19 variants)
- not provided (9 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the CLOCK gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | |||||
| missense | 19 | 21 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| inframe indel | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| splice region ? | 1 | 1 | ||||
| non coding ? | 2 | |||||
| Total | 0 | 0 | 19 | 4 | 4 |
Variants in CLOCK
This is a list of pathogenic ClinVar variants found in the CLOCK region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 4-55435530-T-C | not specified | Uncertain significance (Dec 19, 2022) | ||
| 4-55438451-A-G | not specified | Uncertain significance (Mar 07, 2023) | ||
| 4-55438457-A-G | not specified | Uncertain significance (Mar 04, 2024) | ||
| 4-55438503-C-T | not specified | Uncertain significance (Apr 14, 2023) | ||
| 4-55442441-C-T | not specified | Uncertain significance (Jan 17, 2024) | ||
| 4-55442520-C-T | not specified | Uncertain significance (Feb 28, 2023) | ||
| 4-55443769-A-C | not specified | Uncertain significance (Oct 27, 2023) | ||
| 4-55443770-T-A | not specified | Uncertain significance (Oct 29, 2021) | ||
| 4-55443782-G-A | not specified | Uncertain significance (Oct 06, 2022) | ||
| 4-55443881-A-T | not specified | Uncertain significance (Nov 03, 2022) | ||
| 4-55444697-C-T | not specified | Uncertain significance (Nov 23, 2022) | ||
| 4-55444741-G-A | Likely benign (Aug 30, 2018) | |||
| 4-55449476-T-C | not specified | Uncertain significance (Oct 05, 2023) | ||
| 4-55449478-G-A | Likely benign (Jul 15, 2018) | |||
| 4-55450168-A-G | not specified | Uncertain significance (Nov 27, 2023) | ||
| 4-55450210-T-G | not specified | Uncertain significance (Nov 18, 2022) | ||
| 4-55453044-A-G | Benign (Jul 10, 2017) | |||
| 4-55453103-C-T | not specified | Uncertain significance (Oct 05, 2023) | ||
| 4-55455912-T-C | not specified | Uncertain significance (Oct 25, 2023) | ||
| 4-55455999-G-A | not specified | Uncertain significance (Dec 20, 2023) | ||
| 4-55458938-A-G | not specified | Uncertain significance (Mar 01, 2024) | ||
| 4-55458951-A-G | not specified | Uncertain significance (Nov 06, 2023) | ||
| 4-55458980-C-T | Likely benign (Jun 14, 2018) | |||
| 4-55458985-A-G | Benign (Jul 31, 2018) | |||
| 4-55459020-T-C | Benign (Jul 19, 2018) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| CLOCK | protein_coding | protein_coding | ENST00000309964 | 20 | 119236 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.00 | 0.000431 | 125729 | 0 | 15 | 125744 | 0.0000596 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.83 | 334 | 442 | 0.755 | 0.0000218 | 5581 |
| Missense in Polyphen | 92 | 145.14 | 0.63386 | 1937 | ||
| Synonymous | 0.578 | 144 | 153 | 0.941 | 0.00000762 | 1556 |
| Loss of Function | 5.87 | 7 | 53.1 | 0.132 | 0.00000273 | 593 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000118 | 0.000118 |
| Ashkenazi Jewish | 0.000199 | 0.000198 |
| East Asian | 0.0000546 | 0.0000544 |
| Finnish | 0.0000462 | 0.0000462 |
| European (Non-Finnish) | 0.0000445 | 0.0000440 |
| Middle Eastern | 0.0000546 | 0.0000544 |
| South Asian | 0.0000653 | 0.0000653 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time- keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. Regulates the circadian expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an enhancer of the transactivation potential of NF-kappaB. Plays an important role in the homeostatic regulation of sleep. The CLOCK-ARNTL/BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. The CLOCK-ARNTL2/BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking Ala residue in addition to the canonical 6-nucleotide E-box sequence (PubMed:23229515). CLOCK specifically binds to the half-site 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-3' (PubMed:23229515). The CLOCK- ARNTL/BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' (PubMed:23229515). CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner ARNTL/BMAL1. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation of multiple lysine residues located in its hinge region (PubMed:21980503). The acetyltransferase activity of CLOCK is as important as its transcription activity in circadian control. Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a circadian manner. Facilitated by BMAL1, rhythmically interacts and acetylates argininosuccinate synthase 1 (ASS1) leading to enzymatic inhibition of ASS1 as well as the circadian oscillation of arginine biosynthesis and subsequent ureagenesis (PubMed:28985504). {ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:18587630, ECO:0000269|PubMed:21659603, ECO:0000269|PubMed:21980503, ECO:0000269|PubMed:22284746, ECO:0000269|PubMed:23229515, ECO:0000269|PubMed:23785138, ECO:0000269|PubMed:24005054, ECO:0000269|PubMed:28985504}.;
- Pathway
- Circadian rhythm - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Circadian Clock;miR-targeted genes in epithelium - TarBase;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;Melatonin metabolism and effects;NR1D1 (REV-ERBA) represses gene expression;Exercise-induced Circadian Regulation;Circadian Clock;Chromatin modifying enzymes;BMAL1:CLOCK,NPAS2 activates circadian gene expression;HATs acetylate histones;Chromatin organization;Circadian rhythm pathway
(Consensus)
Recessive Scores
- pRec
- 0.241
Intolerance Scores
- loftool
- 0.496
- rvis_EVS
- -0.53
- rvis_percentile_EVS
- 20.78
Haploinsufficiency Scores
- pHI
- 0.454
- hipred
- Y
- hipred_score
- 0.758
- ghis
- 0.566
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.820
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Clock
- Phenotype
- nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; normal phenotype; reproductive system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; cellular phenotype; homeostasis/metabolism phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype;
Zebrafish Information Network
- Gene name
- clocka
- Affected structure
- nucleate erythrocyte
- Phenotype tag
- abnormal
- Phenotype quality
- decreased amount
Gene ontology
- Biological process
- DNA damage checkpoint;regulation of transcription, DNA-templated;regulation of transcription by RNA polymerase II;protein acetylation;signal transduction;spermatogenesis;circadian rhythm;photoperiodism;histone acetylation;circadian regulation of gene expression;regulation of hair cycle;proteasome-mediated ubiquitin-dependent protein catabolic process;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of inflammatory response;regulation of insulin secretion;positive regulation of NF-kappaB transcription factor activity;response to redox state;cellular response to ionizing radiation;regulation of type B pancreatic cell development;negative regulation of glucocorticoid receptor signaling pathway
- Cellular component
- nucleus;nucleoplasm;transcription factor complex;chromosome;cytosol;chromatoid body;intracellular membrane-bounded organelle
- Molecular function
- RNA polymerase II proximal promoter sequence-specific DNA binding;RNA polymerase II distal enhancer sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;DNA-binding transcription factor activity;histone acetyltransferase activity;protein binding;chromatin DNA binding;sequence-specific DNA binding;protein dimerization activity;E-box binding