TRPM4

transient receptor potential cation channel subfamily M member 4, the group of Transient receptor potential cation channels

Basic information

Region (hg38): 19:49157740-49211836

Links

ENSG00000130529 ∙ NCBI:54795 ∙ OMIM:606936 ∙ HGNC:17993 ∙ Uniprot:Q8TD43 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Brugada syndrome (Limited), mode of inheritance: AD
• progressive familial heart block type IB (Moderate), mode of inheritance: AD
• progressive familial heart block type IB (Moderate), mode of inheritance: AD
• progressive familial heart block (Supportive), mode of inheritance: AD
• erythrokeratodermia variabilis (Supportive), mode of inheritance: AD
• erythrokeratodermia variabilis et progressiva 6 (Limited), mode of inheritance: AD
• progressive familial heart block type IB (Strong), mode of inheritance: AD
• erythrokeratodermia variabilis et progressiva 6 (Strong), mode of inheritance: AD
• Brugada syndrome (Disputed Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Progressive familial heart block, type IB	AD	Cardiovascular	Preventive measures (eg, pacemakers and other medical measures) have been shown to be effective to control sequelae, which can include sudden death	Cardiovascular; Dermatologic	897853; 619595; 4003252; 3750143; 3347879; 9023172; 19726882; 20562447; 21887725; 30528822

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TRPM4 gene.

• Progressive familial heart block type IB (1056 variants)
• Cardiovascular phenotype (599 variants)
• not provided (308 variants)
• not specified (77 variants)
• Progressive familial heart block type IB;Erythrokeratodermia variabilis et progressiva 6 (53 variants)
• Inborn genetic diseases (30 variants)
• Erythrokeratodermia variabilis et progressiva 6;Progressive familial heart block type IB (29 variants)
• Long QT syndrome (7 variants)
• Brugada syndrome (7 variants)
• Cardiomyopathy (6 variants)
• TRPM4-related condition (5 variants)
• Hypertrophic cardiomyopathy (5 variants)
• Erythrokeratodermia variabilis et progressiva 6 (4 variants)
• Progressive familial heart block, type 1A (2 variants)
• Progressive familial heart block (2 variants)
• Sudden cardiac death (2 variants)
• Conduction system disorder (1 variants)
• 7 conditions (1 variants)
• Arrhythmogenic right ventricular cardiomyopathy (1 variants)
• Family history of sudden cardiac death (1 variants)
• Restrictive cardiomyopathy;Cardiomyopathy (1 variants)
• Ventricular fibrillation (1 variants)
• Arrhythmogenic right ventricular cardiomyopathy;Cardiomyopathy (1 variants)
• Cardiac arrest (1 variants)
• Ventricular tachycardia (1 variants)
• Primary dilated cardiomyopathy (1 variants)
• Sudden unexplained death (1 variants)
• Conduction disorder of the heart (1 variants)
• Catecholaminergic polymorphic ventricular tachycardia 1 (1 variants)
• Short QT syndrome (1 variants)
• Wolff-Parkinson-White pattern (1 variants)
• TRPM4-Related Disorders (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TRPM4 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			13	267	6	286
missense		2	656	19		677
nonsense		1	17			18
start loss			4			4
frameshift			46			46
inframe indel			17	1		18
splice donor/acceptor (+/-2bp)			24	1		25
splice region			30	28	1	59
non coding			16	157	70	243
Total	0	3	793	445	76

Highest pathogenic variant AF is 0.00000657

Variants in TRPM4

This is a list of pathogenic ClinVar variants found in the TRPM4 region.

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

Position	Type	Phenotype	Significance	ClinVar
19-49157760-G-T		Progressive familial heart block	Conflicting classifications of pathogenicity (Mar 01, 2023)
19-49157855-G-A		not specified • Progressive familial heart block type IB	Benign (Apr 04, 2023)
19-49157867-A-C		Cardiovascular phenotype	Uncertain significance (Aug 31, 2023)
19-49157867-A-G		Progressive familial heart block type IB	Uncertain significance (Jun 28, 2020)
19-49157868-T-C		Progressive familial heart block type IB	Uncertain significance (Aug 23, 2022)
19-49157869-G-C		Cardiovascular phenotype	Uncertain significance (Aug 14, 2023)
19-49157872-G-T		Cardiovascular phenotype	Likely benign (Oct 28, 2021)
19-49157874-T-C		Progressive familial heart block type IB	Uncertain significance (Oct 13, 2021)
19-49157876-C-T		Progressive familial heart block type IB	Uncertain significance (May 19, 2023)
19-49157877-C-G		Progressive familial heart block type IB;Erythrokeratodermia variabilis et progressiva 6 • Progressive familial heart block type IB	Uncertain significance (Jun 02, 2023)
19-49157878-G-A		not specified • Progressive familial heart block type IB • Cardiovascular phenotype	Likely benign (Dec 30, 2022)
19-49157878-G-C		Cardiovascular phenotype	Likely benign (Jun 09, 2021)
19-49157878-G-T		Progressive familial heart block type IB	Likely benign (Sep 05, 2023)
19-49157879-G-A		Progressive familial heart block type IB • Cardiovascular phenotype	Uncertain significance (Aug 29, 2023)
19-49157880-A-C		Progressive familial heart block type IB	Uncertain significance (Nov 17, 2022)
19-49157884-G-A		Cardiovascular phenotype • Progressive familial heart block type IB	Likely benign (Jul 25, 2023)
19-49157884-G-C		Cardiovascular phenotype	Uncertain significance (May 04, 2023)
19-49157885-G-A		Progressive familial heart block type IB • TRPM4-related disorder	Likely pathogenic (Jul 13, 2023)
19-49157889-A-T		Progressive familial heart block type IB;Erythrokeratodermia variabilis et progressiva 6	Uncertain significance (Aug 13, 2021)
19-49157890-G-A		Progressive familial heart block type IB • Erythrokeratodermia variabilis et progressiva 6;Progressive familial heart block type IB	Uncertain significance (Apr 22, 2022)
19-49157895-G-A		Progressive familial heart block type IB	Uncertain significance (Mar 19, 2022)
19-49157896-C-G		Progressive familial heart block type IB	Conflicting classifications of pathogenicity (Dec 25, 2023)
19-49157897-G-A		not specified • Progressive familial heart block type IB	Likely benign (Oct 30, 2023)
19-49157900-G-A		Progressive familial heart block type IB	Likely benign (Mar 18, 2022)
19-49157900-G-C		Progressive familial heart block type IB	Likely benign (Aug 23, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TRPM4	protein_coding	protein_coding	ENST00000252826	25	54096

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.65e-33	0.000467	124793	1	954	125748	0.00380

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.966	726	803	0.904	0.0000578	7740
Missense in Polyphen		205	239.87	0.85464		2509
Synonymous	1.08	316	341	0.926	0.0000245	2580
Loss of Function	0.900	54	61.6	0.876	0.00000324	619

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00266	0.00258
Ashkenazi Jewish	0.00	0.00
East Asian	0.00599	0.00600
Finnish	0.00781	0.00742
European (Non-Finnish)	0.00502	0.00478
Middle Eastern	0.00599	0.00600
South Asian	0.00154	0.00147
Other	0.00427	0.00408

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Calcium-activated non selective (CAN) cation channel that mediates membrane depolarization (PubMed:12015988, PubMed:29211723). While it is activated by increase in intracellular Ca(2+), it is impermeable to it (PubMed:12015988). Mediates transport of monovalent cations (Na(+) > K(+) > Cs(+) > Li(+)), leading to depolarize the membrane. It thereby plays a central role in cadiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. Participates in T-cell activation by modulating Ca(2+) oscillations after T lymphocyte activation, which is required for NFAT-dependent IL2 production. Involved in myogenic constriction of cerebral arteries. Controls insulin secretion in pancreatic beta-cells. May also be involved in pacemaking or could cause irregular electrical activity under conditions of Ca(2+) overload. Affects T-helper 1 (Th1) and T-helper 2 (Th2) cell motility and cytokine production through differential regulation of calcium signaling and NFATC1 localization. Enhances cell proliferation through up-regulation of the beta-catenin signaling pathway. {ECO:0000269|PubMed:11535825, ECO:0000269|PubMed:12015988, ECO:0000269|PubMed:12799367, ECO:0000269|PubMed:14758478, ECO:0000269|PubMed:15121803, ECO:0000269|PubMed:15331675, ECO:0000269|PubMed:15472118, ECO:0000269|PubMed:15550671, ECO:0000269|PubMed:15590641, ECO:0000269|PubMed:15845551, ECO:0000269|PubMed:16186107, ECO:0000269|PubMed:16407466, ECO:0000269|PubMed:16424899, ECO:0000269|PubMed:16806463, ECO:0000269|PubMed:20625999, ECO:0000269|PubMed:20656926, ECO:0000269|PubMed:29211723}.
• Disease: DISEASE: Progressive familial heart block 1B (PFHB1B) [MIM:604559]: A cardiac bundle branch disorder characterized by progressive alteration of cardiac conduction through the His- Purkinje system, with a pattern of a right bundle-branch block and/or left anterior hemiblock occurring individually or together. It leads to complete atrio-ventricular block causing syncope and sudden death. {ECO:0000269|PubMed:19726882, ECO:0000269|PubMed:20562447, ECO:0000269|PubMed:21887725}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Insulin secretion - Homo sapiens (human);Stimuli-sensing channels;Ion channel transport;Transport of small molecules;TRP channels (Consensus)

Recessive Scores

• pRec: 0.104

Intolerance Scores

• loftool: 0.752
• rvis_EVS: -1.14
• rvis_percentile_EVS: 6.39

Haploinsufficiency Scores

• pHI: 0.145
• hipred: N
• hipred_score: 0.268
• ghis: 0.494

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0981

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Trpm4
• Phenotype: hematopoietic 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); immune system phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: adaptive immune response;dendritic cell chemotaxis;regulation of T cell cytokine production;positive regulation of cytosolic calcium ion concentration;positive regulation of cell population proliferation;positive regulation of heart rate;protein sumoylation;calcium-mediated signaling;negative regulation of bone mineralization;positive regulation of insulin secretion involved in cellular response to glucose stimulus;vasoconstriction;positive regulation of fat cell differentiation;negative regulation of osteoblast differentiation;positive regulation of vasoconstriction;protein homotetramerization;calcium ion transmembrane transport;cellular response to ATP;membrane depolarization during AV node cell action potential;membrane depolarization during Purkinje myocyte cell action potential;membrane depolarization during bundle of His cell action potential;regulation of heart rate by cardiac conduction;positive regulation of canonical Wnt signaling pathway;inorganic cation transmembrane transport;sodium ion import across plasma membrane;regulation of ventricular cardiac muscle cell action potential;positive regulation of atrial cardiac muscle cell action potential;positive regulation of adipose tissue development;positive regulation of regulation of vascular smooth muscle cell membrane depolarization
• Cellular component: nucleoplasm;endoplasmic reticulum;Golgi apparatus;cytosol;plasma membrane;sodium channel complex;neuronal cell body;spanning component of plasma membrane;spanning component of membrane
• Molecular function: calcium activated cation channel activity;calcium channel activity;sodium channel activity;calcium ion binding;calmodulin binding;ATP binding