CALM3

calmodulin 3, the group of Receptor ligands|Phosphorylase kinase subunits|EF-hand domain containing

Basic information

Region (hg38): 19:46601073-46610782

Links

ENSG00000160014 ∙ NCBI:808 ∙ OMIM:114183 ∙ HGNC:1449 ∙ Uniprot:P0DP25 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• long QT syndrome 16 (Strong), mode of inheritance: AD
• long QT syndrome 16 (Strong), mode of inheritance: AD
• catecholaminergic polymorphic ventricular tachycardia (Strong), mode of inheritance: AD
• familial long QT syndrome (Definitive), mode of inheritance: AD
• catecholaminergic polymorphic ventricular tachycardia (Moderate), mode of inheritance: AD
• long QT syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Long QT syndrome 16	AD	Cardiovascular	Individuals may present with severe cardiac manifestations, including arrhythmias, syncope, and sudden death, and surveillance, preventive measures (eg, including avoidance of dangerous or excacerbating factors), and treatment (eg, including medical treatment or ICD placement, which have both been described as beneficial in affected individuals) may allow early and beneficial management	Cardiovascular	25460178; 27516456; 31454269

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CALM3 gene.

• Long QT syndrome 1 (100 variants)
• Cardiovascular phenotype (35 variants)
• not provided (30 variants)
• not specified (13 variants)
• Long QT syndrome 16 (7 variants)
• Congenital long QT syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CALM3 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			1	44	2	47
missense	5	2	20			27
nonsense			1			1
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region			6	6		12
non coding			3	36	9	48
Total	5	2	26	80	11

Variants in CALM3

This is a list of pathogenic ClinVar variants found in the CALM3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-46601258-G-A			Likely benign (Oct 17, 2018)
19-46601278-T-A		Long QT syndrome 1	Benign (Jan 22, 2024)
19-46601406-C-T			Likely benign (May 14, 2018)
19-46601421-C-A		not specified	Benign (Mar 11, 2024)
19-46601429-C-A			Uncertain significance (Apr 21, 2022)
19-46601432-G-A		Cardiovascular phenotype	Uncertain significance (Nov 18, 2020)
19-46601432-G-T			Uncertain significance (Jul 16, 2019)
19-46601448-C-T		Long QT syndrome 1	Likely benign (Jul 25, 2022)
19-46601449-T-TG		Long QT syndrome 1	Benign (Oct 28, 2023)
19-46601450-G-A		Long QT syndrome 1	Likely benign (Sep 08, 2021)
19-46601451-G-C		Long QT syndrome 1	Likely benign (Aug 25, 2023)
19-46601454-G-A		Long QT syndrome 1	Likely benign (Jun 09, 2023)
19-46601455-G-A		Long QT syndrome 1	Likely benign (Nov 30, 2022)
19-46601456-T-G		Long QT syndrome 1	Likely benign (Aug 31, 2023)
19-46601522-A-C			Likely benign (Jun 26, 2018)
19-46605523-G-A			Likely benign (Oct 16, 2018)
19-46605665-G-A			Likely benign (Jul 09, 2018)
19-46605754-T-C		Long QT syndrome 16	Benign (Jul 14, 2021)
19-46605810-C-G		Long QT syndrome 1	Likely benign (Jan 17, 2023)
19-46605821-T-C		Long QT syndrome 1	Likely benign (Jan 17, 2023)
19-46605822-T-C		Long QT syndrome 1	Likely benign (Mar 04, 2019)
19-46605824-C-T		Long QT syndrome 1 • Long QT syndrome 16 • Congenital long QT syndrome	Uncertain significance (Sep 19, 2021)
19-46605835-G-A		Cardiovascular phenotype • Long QT syndrome 1	Likely benign (Nov 27, 2023)
19-46605847-G-A		Long QT syndrome 1	Likely benign (Jul 31, 2023)
19-46605847-G-C		Long QT syndrome 1	Uncertain significance (Aug 17, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CALM3	protein_coding	protein_coding	ENST00000291295	6	9720

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.927	0.0722	125651	0	1	125652	0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.98	9	87.3	0.103	0.00000470	1011
Missense in Polyphen		1	18.614	0.053722		259
Synonymous	-0.180	34	32.7	1.04	0.00000201	251
Loss of Function	2.68	0	8.38	0.00	4.40e-7	98

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000615	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis. {ECO:0000250|UniProtKB:P0DP23, ECO:0000269|PubMed:16760425}.
• Disease: DISEASE: Note=Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare condition caused by mutation in CALM3 that lead to an arrhythmogenic disorder characterized by stress- induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. Patients present with recurrent syncope, seizures, or sudden death after physical activity or emotional stress. {ECO:0000269|PubMed:27516456}.
• Pathway: Inflammatory mediator regulation of TRP channels - Homo sapiens (human);Aldosterone synthesis and secretion - Homo sapiens (human);Oxytocin signaling pathway - Homo sapiens (human);Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Pertussis - Homo sapiens (human);Long-term potentiation - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Oocyte meiosis - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Alzheimer,s disease - Homo sapiens (human);Gastric acid secretion - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Glucagon signaling pathway - Homo sapiens (human);Glioma - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);Fluid shear stress and atherosclerosis - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Renin secretion - Homo sapiens (human);Tuberculosis - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);Salivary secretion - Homo sapiens (human);Phosphatidylinositol signaling system - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Olfactory transduction - Homo sapiens (human);Phototransduction - Homo sapiens (human);Alcoholism - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Melanogenesis - Homo sapiens (human);Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;Alzheimers Disease;Myometrial Relaxation and Contraction Pathways;Ras Signaling;Glycogen Metabolism;Calcium Regulation in the Cardiac Cell;Regulation of Ras family activation;TCR;EGFR1;ErbB1 downstream signaling;BCR signaling pathway;IFN-gamma pathway;Insulin-mediated glucose transport;Downstream signaling in naïve CD8+ T cells;N-cadherin signaling events;Calcineurin-regulated NFAT-dependent transcription in lymphocytes;IL2 signaling events mediated by PI3K;Regulation of cytoplasmic and nuclear SMAD2/3 signaling;p38 MAPK signaling pathway;Role of Calcineurin-dependent NFAT signaling in lymphocytes;Lissencephaly gene (LIS1) in neuronal migration and development;Signaling events mediated by VEGFR1 and VEGFR2;Calcium signaling in the CD4+ TCR pathway;Cellular roles of Anthrax toxin;VEGFR1 specific signals;CD4 T cell receptor signaling-JNK cascade;CD4 T cell receptor signaling (Consensus)

Recessive Scores

• pRec: 0.935

Intolerance Scores

• loftool: 0.475
• rvis_EVS: -0.1
• rvis_percentile_EVS: 46.2

Haploinsufficiency Scores

• hipred: Y
• hipred_score: 0.658
• ghis: 0.622

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.868

Mouse Genome Informatics

• Gene name: Calm3

Gene ontology

• Biological process: G2/M transition of mitotic cell cycle;response to amphetamine;regulation of heart rate;detection of calcium ion;G protein-coupled receptor signaling pathway;activation of adenylate cyclase activity;positive regulation of peptidyl-threonine phosphorylation;negative regulation of peptidyl-threonine phosphorylation;regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum;regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion;substantia nigra development;positive regulation of protein autophosphorylation;regulation of cytokinesis;positive regulation of phosphoprotein phosphatase activity;positive regulation of protein dephosphorylation;positive regulation of DNA binding;positive regulation of nitric-oxide synthase activity;positive regulation of cyclic-nucleotide phosphodiesterase activity;response to corticosterone;response to calcium ion;regulation of cardiac muscle contraction;negative regulation of ryanodine-sensitive calcium-release channel activity;positive regulation of ryanodine-sensitive calcium-release channel activity;positive regulation of protein serine/threonine kinase activity;positive regulation by host of symbiont cAMP-mediated signal transduction;establishment of protein localization to mitochondrial membrane;regulation of synaptic vesicle endocytosis;regulation of high voltage-gated calcium channel activity;regulation of cell communication by electrical coupling involved in cardiac conduction;regulation of synaptic vesicle exocytosis
• Cellular component: spindle pole;nucleus;cytoplasm;centrosome;spindle microtubule;plasma membrane;voltage-gated potassium channel complex;sarcomere;growth cone;synaptic vesicle membrane;mitochondrial membrane;vesicle;protein-containing complex;calcium channel complex;myelin sheath;catalytic complex
• Molecular function: calcium ion binding;protein binding;adenylate cyclase binding;adenylate cyclase activator activity;protein kinase binding;protein domain specific binding;nitric-oxide synthase regulator activity;titin binding;type 3 metabotropic glutamate receptor binding;N-terminal myristoylation domain binding;protein serine/threonine kinase activator activity;phosphatidylinositol 3-kinase binding;ion channel binding;calcium-dependent protein binding;nitric-oxide synthase binding;protein phosphatase activator activity;disordered domain specific binding