SLC12A3

solute carrier family 12 member 3, the group of Solute carrier family 12|MicroRNA protein coding host genes

Basic information

Region (hg38): 16:56865207-56915850

Links

ENSG00000070915 ∙ ∙ OMIM:600968 ∙ HGNC:10912 ∙ Uniprot:P55017 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Gitelman syndrome (Strong), mode of inheritance: AR
• Gitelman syndrome (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Gitelman syndrome	AR	Cardiovascular; Renal	Surveillance for, treatment of, and prevention of electrolyte abnormalities may be beneficial; Individuals with cardiovascular manifestations (eg, arrhythmias such as QTc prolongation) that may warrant interventions have also been described	Cardiovascular; Renal	5929460; 1436349; 81436349; 16120871; 17000984; 17981812; 22009145
Individuals have been reported with cardiovascular manifestations

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SLC12A3 gene.

• not_provided (1367 variants)
• Familial_hypokalemia-hypomagnesemia (685 variants)
• Inborn_genetic_diseases (132 variants)
• not_specified (69 variants)
• SLC12A3-related_disorder (50 variants)
• Bartter_syndrome (16 variants)
• Hypokalemia (3 variants)
• Myalgia (2 variants)
• Renal_tubular_acidosis (2 variants)
• Hypermagnesemia (2 variants)
• Muscle_weakness (2 variants)
• Renal_tubulopathies (1 variants)
• Familial_aortopathy (1 variants)
• Inherited_renal_tubular_disease (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SLC12A3 gene is commonly pathogenic or not. These statistics are base on transcript: NM_001126108.2. 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	3	28	488	2	522
missense	39	156	349	32	1	577
nonsense	42	14	1			57
start loss	3					3
frameshift	76	33	2			111
splice donor/acceptor (+/-2bp)	32	45	2			79
Total	193	251	382	520	3

Highest pathogenic variant AF is 0.0015203538

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SLC12A3	protein_coding	protein_coding	ENST00000438926	26	50644

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.03e-32	0.0000913	125522	0	226	125748	0.000899

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.936	682	617	1.11	0.0000392	6705
Missense in Polyphen		242	232.05	1.0429		2524
Synonymous	-1.08	276	254	1.09	0.0000175	2052
Loss of Function	0.362	50	52.8	0.946	0.00000269	578

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00139	0.00139
Ashkenazi Jewish	0.000199	0.000198
East Asian	0.00141	0.00120
Finnish	0.00	0.00
European (Non-Finnish)	0.00121	0.00120
Middle Eastern	0.00141	0.00120
South Asian	0.00103	0.000980
Other	0.000653	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Electroneutral sodium and chloride ion cotransporter. In kidney distal convoluted tubules, key mediator of sodium and chloride reabsorption (PubMed:21613606, PubMed:22009145). Receptor for the proinflammatory cytokine IL18. Contributes to IL18-induced cytokine production, including IFNG, IL6, IL18 and CCL2. May act either independently of IL18R1, or in a complex with IL18R1 (By similarity). {ECO:0000250|UniProtKB:P59158, ECO:0000269|PubMed:21613606, ECO:0000269|PubMed:22009145}.
• Disease: DISEASE: Gitelman syndrome (GTLMNS) [MIM:263800]: An autosomal recessive disorder characterized by hypokalemic alkalosis in combination with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. Patients are often asymptomatic or present transient periods of muscular weakness and tetany, usually accompanied by abdominal pain, vomiting and fever. The phenotype is highly heterogeneous in terms of age at onset and severity. Cardinal features such as hypocalciuria and hypomagnesemia might also change during the life cycle of a given patient. It has overlapping features with Bartter syndrome. {ECO:0000269|PubMed:10616841, ECO:0000269|PubMed:10988270, ECO:0000269|PubMed:11168953, ECO:0000269|PubMed:11940055, ECO:0000269|PubMed:12008755, ECO:0000269|PubMed:12112667, ECO:0000269|PubMed:15069170, ECO:0000269|PubMed:15687331, ECO:0000269|PubMed:16429844, ECO:0000269|PubMed:17654016, ECO:0000269|PubMed:17873326, ECO:0000269|PubMed:22009145, ECO:0000269|PubMed:26099046, ECO:0000269|PubMed:8528245, ECO:0000269|PubMed:8900229, ECO:0000269|PubMed:8954067, ECO:0000269|PubMed:9734597}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Diuretics Pathway, Pharmacodynamics;Polythiazide Action Pathway;Methyclothiazide Action Pathway;Bumetanide Action Pathway;Spironolactone Action Pathway;Eplerenone Action Pathway;Triamterene Action Pathway;Amiloride Action Pathway;Ethacrynic Acid Action Pathway;Quinethazone Action Pathway;Bendroflumethiazide Action Pathway;Chlorthalidone Action Pathway;Trichlormethiazide Action Pathway;Iminoglycinuria;Lysinuric Protein Intolerance;Blue diaper syndrome;Lysinuric protein intolerance (LPI);Cystinuria;Indapamide Action Pathway;Furosemide Action Pathway;Torsemide Action Pathway;Hartnup Disorder;Glucose Transporter Defect (SGLT2);Kidney Function;Glucose Transporter Defect (SGLT2);Metolazone Action Pathway;Hydrochlorothiazide Action Pathway;Cyclothiazide Action Pathway;Hydroflumethiazide Action Pathway;Chlorothiazide Action Pathway;Cation-coupled Chloride cotransporters;Transport of inorganic cations/anions and amino acids/oligopeptides;SLC-mediated transmembrane transport;Transport of small molecules (Consensus)

Recessive Scores

• pRec: 0.278

Intolerance Scores

• loftool: 0.0228
• rvis_EVS: -1.62
• rvis_percentile_EVS: 2.89

Haploinsufficiency Scores

• pHI: 0.238
• hipred: N
• hipred_score: 0.251
• ghis: 0.516

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.911

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Slc12a3
• Phenotype: renal/urinary 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); homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: slc12a3
• Affected structure: pronephric duct
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: ion transport;sodium ion transport;cell volume homeostasis;sodium ion transmembrane transport;chloride ion homeostasis;potassium ion homeostasis;sodium ion homeostasis;chloride transmembrane transport;potassium ion import across plasma membrane
• Cellular component: cytosol;plasma membrane;integral component of plasma membrane;membrane;apical plasma membrane;extracellular exosome
• Molecular function: transporter activity;protein binding;sodium:potassium:chloride symporter activity;sodium ion transmembrane transporter activity;sodium:chloride symporter activity;potassium:chloride symporter activity