CNR1
cannabinoid receptor 1, the group of Cannabinoid receptors
Basic information
Region (hg38): 6:88139863-88166347
Previous symbols: [ "CNR" ]
Links
Phenotypes
GenCC
Source:
No genCC data.
ClinVar
This is a list of variants' phenotypes submitted to
- not provided (7 variants)
- Inborn genetic diseases (7 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the CNR1 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 | 7 | |||||
| missense | 7 | |||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| inframe indel | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| splice region ? | 0 | |||||
| non coding ? | 0 | |||||
| Total | 0 | 0 | 7 | 6 | 1 |
Variants in CNR1
This is a list of pathogenic ClinVar variants found in the CNR1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 6-88143874-C-T | Likely benign (May 29, 2018) | |||
| 6-88143939-C-T | not specified | Uncertain significance (Nov 22, 2023) | ||
| 6-88143950-A-C | not specified | Uncertain significance (Sep 12, 2023) | ||
| 6-88144144-C-A | Likely benign (Jun 19, 2018) | |||
| 6-88144146-T-C | not specified | Uncertain significance (Jul 13, 2021) | ||
| 6-88144183-C-T | Likely benign (May 31, 2018) | |||
| 6-88144223-A-G | not specified | Uncertain significance (Oct 10, 2023) | ||
| 6-88144224-C-A | not specified | Uncertain significance (Mar 07, 2024) | ||
| 6-88144360-G-C | CNR1-related disorder | Likely benign (Dec 04, 2019) | ||
| 6-88144363-G-A | Benign (Feb 06, 2019) | |||
| 6-88144404-C-G | not specified | Uncertain significance (Feb 23, 2023) | ||
| 6-88144531-G-A | CNR1-related disorder | Likely benign (May 02, 2019) | ||
| 6-88144594-A-T | Likely benign (Oct 09, 2018) | |||
| 6-88144795-C-T | Likely benign (Jul 27, 2018) | |||
| 6-88144806-C-T | not specified | Uncertain significance (Feb 06, 2024) | ||
| 6-88144842-G-T | not specified | Uncertain significance (Nov 18, 2022) | ||
| 6-88145014-C-T | Likely benign (Aug 16, 2018) | |||
| 6-88145019-G-A | not specified | Uncertain significance (May 04, 2023) | ||
| 6-88145084-G-A | not specified | Uncertain significance (Mar 21, 2023) | ||
| 6-88145090-A-G | not specified | Uncertain significance (Sep 26, 2023) | ||
| 6-88145164-C-T | not specified | Uncertain significance (Feb 15, 2023) | ||
| 6-88145245-A-G | CNR1-related disorder | Likely benign (Aug 14, 2019) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| CNR1 | protein_coding | protein_coding | ENST00000537554 | 1 | 26496 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.507 | 0.490 | 125740 | 0 | 8 | 125748 | 0.0000318 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 2.62 | 165 | 291 | 0.568 | 0.0000175 | 3128 |
| Missense in Polyphen | 50 | 136.36 | 0.36669 | 1458 | ||
| Synonymous | -0.428 | 134 | 128 | 1.05 | 0.00000871 | 974 |
| Loss of Function | 2.42 | 2 | 10.5 | 0.191 | 5.32e-7 | 120 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00 | 0.00 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.0000616 | 0.0000615 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.00 | 0.00 |
| Other | 0.000163 | 0.000163 |
dbNSFP
Source:
- Function
- FUNCTION: G-protein coupled receptor for endogenous cannabinoids (eCBs), including N-arachidonoylethanolamide (also called anandamide or AEA) and 2-arachidonoylglycerol (2-AG), as well as phytocannabinoids, such as delta(9)-tetrahydrocannabinol (THC) (PubMed:15620723, PubMed:27768894, PubMed:27851727). Mediates many cannabinoid-induced effects, acting, among others, on food intake, memory loss, gastrointestinal motility, catalepsy, ambulatory activity, anxiety, chronic pain. Signaling typically involves reduction in cyclic AMP (PubMed:1718258, PubMed:21895628, PubMed:27768894). In the hypothalamus, may have a dual effect on mitochondrial respiration depending upon the agonist dose and possibly upon the cell type. Increases respiration at low doses, while decreases respiration at high doses. At high doses, CNR1 signal transduction involves G-protein alpha-i protein activation and subsequent inhibition of mitochondrial soluble adenylate cyclase, decrease in cyclic AMP concentration, inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system, including NDUFS2. In the hypothalamus, inhibits leptin-induced reactive oxygen species (ROS) formation and mediates cannabinoid-induced increase in SREBF1 and FASN gene expression. In response to cannabinoids, drives the release of orexigenic beta-endorphin, but not that of melanocyte-stimulating hormone alpha/alpha-MSH, from hypothalamic POMC neurons, hence promoting food intake. In the hippocampus, regulates cellular respiration and energy production in response to cannabinoids. Involved in cannabinoid-dependent depolarization-induced suppression of inhibition (DSI), a process in which depolarization of CA1 postsynaptic pyramidal neurons mobilizes eCBs, which retrogradely activate presynaptic CB1 receptors, transiently decreasing GABAergic inhibitory neurotransmission. Also reduces excitatory synaptic transmission (By similarity). In superior cervical ganglions and cerebral vascular smooth muscle cells, inhibits voltage-gated Ca(2+) channels in a constitutive, as well as agonist-dependent manner (PubMed:17895407). In cerebral vascular smooth muscle cells, cannabinoid-induced inhibition of voltage-gated Ca(2+) channels leads to vasodilation and decreased vascular tone (By similarity). Induces leptin production in adipocytes and reduces LRP2-mediated leptin clearance in the kidney, hence participating in hyperleptinemia. In adipose tissue, CNR1 signaling leads to increased expression of SREBF1, ACACA and FASN genes (By similarity). In the liver, activation by endocannabinoids leads to increased de novo lipogenesis and reduced fatty acid catabolism, associated with increased expression of SREBF1/SREBP-1, GCK, ACACA, ACACB and FASN genes. May also affect de novo cholesterol synthesis and HDL-cholesteryl ether uptake. Peripherally modulates energy metabolism (By similarity). In high carbohydrate diet- induced obesity, may decrease the expression of mitochondrial dihydrolipoyl dehydrogenase/DLD in striated muscles, as well as that of selected glucose/ pyruvate metabolic enzymes, hence affecting energy expenditure through mitochondrial metabolism (By similarity). In response to cannabinoid anandamide, elicits a proinflammatory response in macrophages, which involves NLRP3 inflammasome activation and IL1B and IL18 secretion (By similarity). In macrophages infiltrating pancreatic islets, this process may participate in the progression of type-2 diabetes and associated loss of pancreatic beta-cells (PubMed:23955712). {ECO:0000250|UniProtKB:O02777, ECO:0000250|UniProtKB:P47746, ECO:0000269|PubMed:15620723, ECO:0000269|PubMed:1718258, ECO:0000269|PubMed:17895407, ECO:0000269|PubMed:21895628, ECO:0000269|PubMed:23955712, ECO:0000269|PubMed:27768894, ECO:0000269|PubMed:27851727}.; FUNCTION: Isoform 2: Only binds 2-AG with high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an inverse agonist on isoform 2 in assays measuring GTP binding to membranes. {ECO:0000269|PubMed:15620723}.;
- Disease
- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269|PubMed:18177726}. Note=The protein represented in this entry may be involved in disease pathogenesis. May contribute to the development of diet-induced obesity and several obesity-associated features, such as dyslipidemia and liver steatosis, regulating peripheral lipogenesis, energy expenditure and feeding behavior. CNR1 inverse agonists have been shown to reduce body weight and improve metabolic abnormalities in obese subjects, although adverse neuropsychiatric effects, including anxiety, irritability, and depressed mood, halted their therapeutic development (PubMed:18177726). In obese mice, peripherally restricted CNR1 inverse agonists have been shown to normalize metabolic abnormalities, including insulin resistance and fatty liver, and to reverse leptin resistance. {ECO:0000269|PubMed:18177726}.;
- Pathway
- Retrograde endocannabinoid signaling - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Neuroactive ligand-receptor interaction - Homo sapiens (human);GPCRs, Other;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Small Ligand GPCRs;Cell-type Dependent Selectivity of CCK2R Signaling;Cannabinoid receptor signaling;Gastric ulcer formation;GPCRs, Class A Rhodopsin-like;Signaling by GPCR;Signal Transduction;metabolism of anandamide an endogenous cannabinoid;Class A/1 (Rhodopsin-like receptors);GPCR ligand binding;G alpha (i) signalling events;GPCR downstream signalling;N-cadherin signaling events
(Consensus)
Recessive Scores
- pRec
- 0.203
Intolerance Scores
- loftool
- 0.351
- rvis_EVS
- -0.96
- rvis_percentile_EVS
- 9.09
Haploinsufficiency Scores
- pHI
- 0.444
- hipred
- Y
- hipred_score
- 0.609
- ghis
- 0.574
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.774
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Cnr1
- Phenotype
- digestive/alimentary 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); skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); growth/size/body region phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); 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); normal phenotype; reproductive system phenotype; homeostasis/metabolism phenotype; cellular phenotype; taste/olfaction phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan);
Zebrafish Information Network
- Gene name
- cnr1
- Affected structure
- hepatocyte
- Phenotype tag
- abnormal
- Phenotype quality
- decreased amount
Gene ontology
- Biological process
- positive regulation of acute inflammatory response to antigenic stimulus;G protein-coupled receptor signaling pathway;G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger;adenylate cyclase-modulating G protein-coupled receptor signaling pathway;spermatogenesis;axonal fasciculation;aging;response to nutrient;memory;positive regulation of neuron projection development;sensory perception of pain;positive regulation of fever generation;negative regulation of fatty acid beta-oxidation;regulation of synaptic transmission, GABAergic;response to lipopolysaccharide;negative regulation of mast cell activation;negative regulation of dopamine secretion;response to nicotine;cannabinoid signaling pathway;response to cocaine;glucose homeostasis;positive regulation of apoptotic process;response to morphine;response to ethanol;negative regulation of action potential;negative regulation of blood pressure;positive regulation of blood pressure;regulation of insulin secretion;negative regulation of nitric-oxide synthase activity;regulation of synaptic transmission, glutamatergic;maternal process involved in female pregnancy;regulation of feeding behavior;regulation of penile erection;retrograde trans-synaptic signaling by endocannabinoid;trans-synaptic signaling by endocannabinoid, modulating synaptic transmission;induction of synaptic vesicle exocytosis by positive regulation of presynaptic cytosolic calcium ion concentration
- Cellular component
- mitochondrial outer membrane;plasma membrane;integral component of plasma membrane;growth cone;integral component of mitochondrial membrane;membrane raft;glutamatergic synapse;GABA-ergic synapse;integral component of presynaptic membrane
- Molecular function
- cannabinoid receptor activity;protein binding;drug binding;voltage-gated calcium channel activity involved in positive regulation of presynaptic cytosolic calcium levels