CASR

calcium sensing receptor, the group of Calcium sensing receptors

Basic information

Region (hg38): 3:122183668-122291629

Previous symbols: [ "HHC", "HHC1" ]

Links

ENSG00000036828 ∙ NCBI:846 ∙ OMIM:601199 ∙ HGNC:1514 ∙ Uniprot:P41180 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant hypocalcemia 1 (Definitive), mode of inheritance: AD
• familial hypocalciuric hypercalcemia 1 (Strong), mode of inheritance: AD
• neonatal severe primary hyperparathyroidism (Supportive), mode of inheritance: AR
• autosomal dominant hypocalcemia (Supportive), mode of inheritance: AD
• familial hypocalciuric hypercalcemia 1 (Supportive), mode of inheritance: AD
• familial hypocalciuric hypercalcemia 1 (Definitive), mode of inheritance: AD
• epilepsy, idiopathic generalized, susceptibility to, 8 (Limited), mode of inheritance: AD
• familial hypocalciuric hypercalcemia 1 (Strong), mode of inheritance: AD
• neonatal severe primary hyperparathyroidism (Strong), mode of inheritance: AD
• autosomal dominant hypocalcemia 1 (Strong), mode of inheritance: AD
• neonatal severe primary hyperparathyroidism (Strong), mode of inheritance: AR
• neonatal severe primary hyperparathyroidism (Definitive), mode of inheritance: AR
• familial hypocalciuric hypercalcemia 1 (Definitive), mode of inheritance: AD
• epilepsy (Disputed Evidence), mode of inheritance: AD
• autosomal dominant hypocalcemia 1 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hyperparathyroidism, neonatal; Hypocalcemia, autosomal dominant 1; Hypocalciuric hypercalcemia, type I; Hyperparathyroidism, neonatal severe primary; Hypoparathyroidism, familial isolated; Hyperparathyroidism, familial primary	AD/AR	Endocrine; Renal	Sequelae, which can be severe in some individuals with hyperparathyrodism, can include seizures, and treatment (eg, with Vitamin D and calcium) can be effective at preventing morbidity; Early diagnosis of NSPHT is critical as the disorder can neurologically devastating or lethal without parathyroidectomy; In some forms of hypoparathyroidism, treatment of hypocalcemia with vitamin D/ vitamin D metabolites can cause hypercalciuria and resultant renal impairment, and PTH injections or diuretic treatment may be effective; In familial hypocalciuric hypercalcemia, accurate diagnosis may be important in order to decrease the use of unhelpful therapies	Endocrine; Musculoskeletal; Neurologic; Renal	18887540; 14089114; 5013415; 830920; 619857; 7054696; 3966479; 7916660; 7874174; 7673400; 7726161; 8132750; 8675635; 8733126; 8813042; 9109436; 9011580; 9253358; 9642634; 9661634; 11013439; 10770217; 11134112; 11701698; 11293637; 12107202; 12241879; 12915654; 15579740; 15241791; 16608894; 17698911; 17018660; 18328986; 18756473; 21986511; 19250271; 22315359

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CASR gene.

• Autosomal_dominant_hypocalcemia_1 (2220 variants)
• Familial_hypocalciuric_hypercalcemia (2194 variants)
• Nephrolithiasis/nephrocalcinosis (1388 variants)
• not_provided (327 variants)
• Familial_hypocalciuric_hypercalcemia_1 (299 variants)
• Neonatal_severe_primary_hyperparathyroidism (249 variants)
• Epilepsy,_idiopathic_generalized,_susceptibility_to,_8 (202 variants)
• not_specified (182 variants)
• CASR-related_disorder (75 variants)
• Familial_hypoparathyroidism (39 variants)
• Hereditary_cancer-predisposing_syndrome (14 variants)
• Bartter_syndrome_with_hypocalcemia (8 variants)
• Autosomal_dominant_hypocalcemia (5 variants)
• Hypercalcemia (5 variants)
• Inborn_genetic_diseases (3 variants)
• Hypocalcemia (2 variants)
• See_cases (2 variants)
• Familial_hypokalemia-hypomagnesemia (1 variants)
• Prostate_cancer (1 variants)
• CASR-related_calcium_metabolism_disorders (1 variants)
• Primary_hyperparathyroidism (1 variants)
• Bartter_disease_type_3 (1 variants)
• Neurodevelopmental_disorder (1 variants)
• Parathyroid_gland_adenoma (1 variants)
• Hypercalcaemia,_hypocalciuric (1 variants)
• Hypertrophic_cardiomyopathy (1 variants)
• Bartter_syndrome (1 variants)
• Idiopathic_generalized_epilepsy (1 variants)
• Hypocalciuria (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CASR gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000388.4. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	1	1	8	863	1	874
missense	51	115	1454	68	1	1689
nonsense	36	13	10			59
start loss	1	3				4
frameshift	71	17	13			101
splice donor/acceptor (+/-2bp)	8	13				21
Total	168	162	1485	931	2

Highest pathogenic variant AF is 0.000021065362

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CASR	protein_coding	protein_coding	ENST00000498619	6	102813

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0467	0.953	125726	1	21	125748	0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.12	399	617	0.646	0.0000382	7179
Missense in Polyphen		111	275.4	0.40304		3204
Synonymous	0.117	264	266	0.991	0.0000180	2180
Loss of Function	4.17	10	37.6	0.266	0.00000231	410

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000247	0.000246
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000217	0.000217
Finnish	0.00	0.00
European (Non-Finnish)	0.0000352	0.0000352
Middle Eastern	0.000217	0.000217
South Asian	0.000294	0.000261
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis (PubMed:7759551, PubMed:8702647, PubMed:8636323, PubMed:8878438, PubMed:17555508, PubMed:19789209, PubMed:21566075, PubMed:22114145, PubMed:23966241, PubMed:25292184, PubMed:25104082, PubMed:26386835, PubMed:25766501, PubMed:22789683). Senses fluctuations in the circulating calcium concentration and modulates the production of parathyroid hormone (PTH) in parathyroid glands (By similarity). The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol- calcium second messenger system (PubMed:7759551). The G-protein- coupled receptor activity is activated by a co-agonist mechanism: aromatic amino acids, such as Trp or Phe, act concertedly with divalent cations, such as calcium or magnesium, to achieve full receptor activation (PubMed:27434672, PubMed:27386547). {ECO:0000250|UniProtKB:Q9QY96, ECO:0000269|PubMed:17555508, ECO:0000269|PubMed:19789209, ECO:0000269|PubMed:21566075, ECO:0000269|PubMed:22114145, ECO:0000269|PubMed:22789683, ECO:0000269|PubMed:23966241, ECO:0000269|PubMed:25104082, ECO:0000269|PubMed:25292184, ECO:0000269|PubMed:25766501, ECO:0000269|PubMed:26386835, ECO:0000269|PubMed:27386547, ECO:0000269|PubMed:27434672, ECO:0000269|PubMed:7759551, ECO:0000269|PubMed:8636323, ECO:0000269|PubMed:8702647, ECO:0000269|PubMed:8878438}.
• Disease: DISEASE: Hypocalciuric hypercalcemia, familial 1 (HHC1) [MIM:145980]: A form of hypocalciuric hypercalcemia, a disorder of mineral homeostasis that is transmitted as an autosomal dominant trait with a high degree of penetrance. It is characterized biochemically by lifelong elevation of serum calcium concentrations and is associated with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone level. Hypermagnesemia is typically present. Affected individuals are usually asymptomatic and the disorder is considered benign. However, chondrocalcinosis and pancreatitis occur in some adults. {ECO:0000269|PubMed:11762699, ECO:0000269|PubMed:15572418, ECO:0000269|PubMed:15579740, ECO:0000269|PubMed:15879434, ECO:0000269|PubMed:16598859, ECO:0000269|PubMed:16740594, ECO:0000269|PubMed:17473068, ECO:0000269|PubMed:17698911, ECO:0000269|PubMed:19179454, ECO:0000269|PubMed:19789209, ECO:0000269|PubMed:21566075, ECO:0000269|PubMed:21643651, ECO:0000269|PubMed:22114145, ECO:0000269|PubMed:23169696, ECO:0000269|PubMed:23966241, ECO:0000269|PubMed:25104082, ECO:0000269|PubMed:25292184, ECO:0000269|PubMed:26386835, ECO:0000269|PubMed:27434672, ECO:0000269|PubMed:7673400, ECO:0000269|PubMed:7726161, ECO:0000269|PubMed:7916660, ECO:0000269|PubMed:8636323, ECO:0000269|PubMed:8702647, ECO:0000269|PubMed:8878438, ECO:0000269|PubMed:9298824}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hyperparathyroidism, neonatal severe (NSHPT) [MIM:239200]: A disorder characterized by severe hypercalcemia, bone demineralization, and failure to thrive usually manifesting in the first 6 months of life. If untreated, NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy. {ECO:0000269|PubMed:14985373, ECO:0000269|PubMed:15572418, ECO:0000269|PubMed:17555508, ECO:0000269|PubMed:27434672, ECO:0000269|PubMed:8675635, ECO:0000269|PubMed:8878438, ECO:0000269|PubMed:9253359}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hypocalcemia, autosomal dominant 1 (HYPOC1) [MIM:601198]: A disorder of mineral homeostasis characterized by blood calcium levels below normal, and low or normal serum parathyroid hormone concentrations. Disease manifestations include mild or asymptomatic hypocalcemia, paresthesias, carpopedal spasm, seizures, hypercalciuria with nephrocalcinosis or kidney stones, and ectopic and basal ganglia calcifications. Few patients manifest hypocalcemia and features of Bartter syndrome, including hypomagnesemia, hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronemia. {ECO:0000269|PubMed:10487661, ECO:0000269|PubMed:12050233, ECO:0000269|PubMed:12107202, ECO:0000269|PubMed:12241879, ECO:0000269|PubMed:12574188, ECO:0000269|PubMed:12915654, ECO:0000269|PubMed:15551332, ECO:0000269|PubMed:16608894, ECO:0000269|PubMed:19179454, ECO:0000269|PubMed:22789683, ECO:0000269|PubMed:23169696, ECO:0000269|PubMed:23966241, ECO:0000269|PubMed:25766501, ECO:0000269|PubMed:7874174, ECO:0000269|PubMed:8702647, ECO:0000269|PubMed:8733126, ECO:0000269|PubMed:8813042, ECO:0000269|PubMed:8878438, ECO:0000269|PubMed:9253358, ECO:0000269|PubMed:9661634, ECO:0000269|PubMed:9920108}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epilepsy, idiopathic generalized 8 (EIG8) [MIM:612899]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Seizure types are variable, but include myoclonic seizures, absence seizures, febrile seizures, complex partial seizures, and generalized tonic-clonic seizures. {ECO:0000269|PubMed:18756473}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: NOD-like receptor signaling pathway - Homo sapiens (human);Proton Pump Inhibitor Pathway, Pharmacodynamics;GPCRs, Class C Metabotropic glutamate, pheromone;Signaling by GPCR;Signal Transduction;Class C/3 (Metabotropic glutamate/pheromone receptors);GPCR ligand binding;E-cadherin signaling in keratinocytes;G alpha (i) signalling events;G alpha (q) signalling events;GPCR downstream signalling (Consensus)

Recessive Scores

• pRec: 0.661

Intolerance Scores

• loftool: 0.00530
• rvis_EVS: -0.11
• rvis_percentile_EVS: 45.57

Haploinsufficiency Scores

• pHI: 0.262
• hipred: Y
• hipred_score: 0.693
• ghis: 0.447

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.711

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Casr
• Phenotype: muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region 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); 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); pigmentation phenotype; endocrine/exocrine gland phenotype; digestive/alimentary phenotype; vision/eye phenotype; immune system phenotype; renal/urinary system phenotype; skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype

Zebrafish Information Network

• Gene name: casr
• Affected structure: cranial vault
• Phenotype tag: abnormal
• Phenotype quality: dorso-ventrally flattened

Gene ontology

• Biological process: ossification;response to ischemia;detection of calcium ion;cellular calcium ion homeostasis;apoptotic process;G protein-coupled receptor signaling pathway;adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway;phospholipase C-activating G protein-coupled receptor signaling pathway;JNK cascade;chemosensory behavior;positive regulation of cell population proliferation;anatomical structure morphogenesis;positive regulation of gene expression;positive regulation of insulin secretion;positive regulation of ATPase activity;bile acid secretion;cellular response to hepatocyte growth factor stimulus;vasodilation;positive regulation of vasoconstriction;branching morphogenesis of an epithelial tube;positive regulation of positive chemotaxis;regulation of calcium ion transport;fat pad development;calcium ion import;cellular response to vitamin D;cellular response to glucose stimulus;cellular response to low-density lipoprotein particle stimulus;cellular response to hypoxia;response to fibroblast growth factor;positive regulation of calcium ion import;cellular response to peptide;chloride transmembrane transport
• Cellular component: nucleus;cytoplasm;plasma membrane;integral component of plasma membrane;cell surface;basolateral plasma membrane;apical plasma membrane;neuronal cell body;axon terminus
• Molecular function: magnesium ion binding;phosphatidylinositol phospholipase C activity;G protein-coupled receptor activity;integrin binding;calcium ion binding;protein binding;drug binding;amino acid binding;polyamine binding;protein kinase binding;signaling receptor activity;protein homodimerization activity;ion channel binding