CRY1
cryptochrome circadian regulator 1
Basic information
Region (hg38): 12:106991364-107093549
Previous symbols: [ "PHLL1" ]
Links
Phenotypes
GenCC
Source:
No genCC data.
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Delayed sleep phase syndrome, susceptibility to | AD | General | 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 | Neurologic | 28388406 |
ClinVar
This is a list of variants' phenotypes submitted to
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the CRY1 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 | 6 | |||||
| missense | 24 | 24 | ||||
| nonsense | 1 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| inframe indel | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| splice region | 0 | |||||
| non coding | 1 | |||||
| Total | 0 | 0 | 25 | 5 | 2 |
Variants in CRY1
This is a list of pathogenic ClinVar variants found in the CRY1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 12-106992962-T-G | Delayed sleep phase syndrome, susceptibility to • Sleep-wake schedule disorder, delayed phase type;Attention deficit hyperactivity disorder | association; risk factor (Jul 01, 2020) | ||
| 12-106992978-G-C | not specified | Uncertain significance (Jun 23, 2023) | ||
| 12-106992993-G-C | not specified | Uncertain significance (Jun 09, 2022) | ||
| 12-106993023-C-T | CRY1-related disorder | Likely benign (Dec 06, 2019) | ||
| 12-106997371-A-G | not specified | Uncertain significance (Oct 22, 2021) | ||
| 12-106997376-T-A | CRY1-related disorder | Benign (May 21, 2018) | ||
| 12-106997511-T-C | not specified | Uncertain significance (Dec 07, 2021) | ||
| 12-106997581-G-T | not specified | Uncertain significance (Apr 12, 2024) | ||
| 12-106997667-C-A | not specified | Uncertain significance (Oct 04, 2024) | ||
| 12-106997949-C-G | not specified | Uncertain significance (Aug 17, 2021) | ||
| 12-106997978-A-C | not specified | Uncertain significance (Oct 04, 2022) | ||
| 12-106998033-T-C | not specified | Uncertain significance (May 13, 2024) | ||
| 12-106999654-G-A | not specified | Uncertain significance (Mar 13, 2023) | ||
| 12-106999664-C-T | CRY1-related disorder | Uncertain significance (Apr 02, 2024) | ||
| 12-106999667-C-T | not specified | Uncertain significance (May 20, 2024) | ||
| 12-106999695-C-T | CRY1-related disorder | Benign (Dec 11, 2017) | ||
| 12-106999715-C-G | not specified | Uncertain significance (Apr 01, 2024) | ||
| 12-106999791-T-C | CRY1-related disorder | Likely benign (May 01, 2019) | ||
| 12-106999816-A-G | not specified | Uncertain significance (Jul 14, 2023) | ||
| 12-106999941-C-T | Sleep-wake schedule disorder, delayed phase type;Attention deficit hyperactivity disorder | association (Jul 01, 2020) | ||
| 12-106999988-A-C | not specified | Uncertain significance (Mar 18, 2024) | ||
| 12-107000000-C-T | not specified | Uncertain significance (Aug 12, 2021) | ||
| 12-107000001-G-A | CRY1-related disorder | Uncertain significance (Nov 02, 2022) | ||
| 12-107000045-G-A | not specified | Uncertain significance (Feb 15, 2023) | ||
| 12-107001328-A-G | CRY1-related disorder | Benign (Oct 17, 2019) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| CRY1 | protein_coding | protein_coding | ENST00000008527 | 12 | 102466 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.66e-9 | 0.990 | 125698 | 0 | 49 | 125747 | 0.000195 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.61 | 241 | 322 | 0.748 | 0.0000164 | 3828 |
| Missense in Polyphen | 98 | 146.52 | 0.66883 | 1768 | ||
| Synonymous | -0.703 | 119 | 110 | 1.09 | 0.00000523 | 1112 |
| Loss of Function | 2.44 | 20 | 35.7 | 0.560 | 0.00000214 | 379 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000274 | 0.000272 |
| Ashkenazi Jewish | 0.000106 | 0.0000992 |
| East Asian | 0.000163 | 0.000163 |
| Finnish | 0.0000929 | 0.0000924 |
| European (Non-Finnish) | 0.000215 | 0.000211 |
| Middle Eastern | 0.000163 | 0.000163 |
| South Asian | 0.000400 | 0.000359 |
| Other | 0.000331 | 0.000326 |
dbNSFP
Source:
- Function
- FUNCTION: Transcriptional repressor 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. CRY1 and CRY2 have redundant functions but also differential and selective contributions at least in defining the pace of the SCN circadian clock and its circadian transcriptional outputs. More potent transcriptional repressor in cerebellum and liver than CRY2, though more effective in lengthening the period of the SCN oscillator. On its side, CRY2 seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY2, is dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. Interacts with CLOCK-ARNTL/BMAL1 independently of PER proteins and is found at CLOCK-ARNTL/BMAL1-bound sites, suggesting that CRY may act as a molecular gatekeeper to maintain CLOCK-ARNTL/BMAL1 in a poised and repressed state until the proper time for transcriptional activation. Represses the CLOCK- ARNTL/BMAL1 induced transcription of BHLHE40/DEC1. Represses the CLOCK-ARNTL/BMAL1 induced transcription of ATF4, MTA1, KLF10 and NAMPT (By similarity). May repress circadian target genes expression in collaboration with HDAC1 and HDAC2 through histone deacetylation. Mediates the clock-control activation of ATR and modulates ATR-mediated DNA damage checkpoint. In liver, mediates circadian regulation of cAMP signaling and gluconeogenesis by binding to membrane-coupled G proteins and blocking glucagon- mediated increases in intracellular cAMP concentrations and CREB1 phosphorylation. Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). Plays a key role in glucose and lipid metabolism modulation, in part, through the transcriptional regulation of genes involved in these pathways, such as LEP or ACSL4. {ECO:0000250|UniProtKB:P97784, ECO:0000269|PubMed:10531061, ECO:0000269|PubMed:14672706, ECO:0000269|PubMed:22170608, ECO:0000269|PubMed:23133559, ECO:0000269|PubMed:28388406}.;
- Disease
- DISEASE: Delayed sleep phase syndrome (DSPS) [MIM:614163]: A circadian rhythm sleep disorder characterized by sleep-onset insomnia and difficulty in awakening at the desired time. Patients with DSPS have chronic difficulty in adjusting their sleep-onset and wake-up times to occupational, school, and social activities. {ECO:0000269|PubMed:28388406}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. An adenine-to-cytosine transversion within the 5'splice site following exon 11 has been found in multiple members of a DSPD family and segregates with the disorder with autosomal dominant inheritance pattern. This variant is predicted to cause exon 11 skipping and in-frame deletion of 24 residues in the C- terminal region of CRY1. Functional studies show that the mutated protein acts as a more potent transcriptional repressor than wild- type, causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms. {ECO:0000269|PubMed:28388406}.;
- Pathway
- Circadian rhythm - Homo sapiens (human);Circadian Clock;Melatonin metabolism and effects;BMAL1-CLOCK,NPAS2 activates circadian gene expression;Exercise-induced Circadian Regulation;Circadian Clock;Circadian rhythm pathway
(Consensus)
Recessive Scores
- pRec
- 0.223
Intolerance Scores
- loftool
- 0.351
- rvis_EVS
- -0.89
- rvis_percentile_EVS
- 10.3
Haploinsufficiency Scores
- pHI
- 0.549
- hipred
- Y
- hipred_score
- 0.706
- ghis
- 0.616
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.918
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Cry1
- 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; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); homeostasis/metabolism phenotype; muscle phenotype; vision/eye 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); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; skeleton 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);
Gene ontology
- Biological process
- negative regulation of transcription by RNA polymerase II;gluconeogenesis;DNA damage induced protein phosphorylation;blue light signaling pathway;protein-chromophore linkage;lipid storage;negative regulation of protein ubiquitination;response to insulin;circadian regulation of gene expression;response to glucagon;glucose homeostasis;regulation of circadian rhythm;negative regulation of circadian rhythm;entrainment of circadian clock by photoperiod;negative regulation of gluconeogenesis;negative regulation of G protein-coupled receptor signaling pathway;negative regulation of transcription, DNA-templated;regulation of DNA damage checkpoint;negative regulation of glucocorticoid receptor signaling pathway;negative regulation of glucocorticoid secretion
- Cellular component
- nucleus;mitochondrion
- Molecular function
- nucleotide binding;DNA binding;double-stranded DNA binding;deoxyribodipyrimidine photo-lyase activity;DNA (6-4) photolyase activity;protein binding;blue light photoreceptor activity;protein kinase binding;phosphatase binding;nuclear hormone receptor binding;histone deacetylase binding;E-box binding