SLC12A1

protein-coding

solute carrier family 12 member 1, the group of Solute carrier family 12

Gene summary

This gene encodes a kidney-specific sodium-potassium-chloride cotransporter that is expressed on the luminal membrane of renal epithelial cells of the thick ascending limb of Henle's loop and the macula densa. It plays a key role in concentrating urine and accounts for most of the NaCl resorption. It is sensitive to such diuretics as furosemide and bumetanide. Some Bartter-like syndromes result from defects in this gene. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their biological validity in humans has not been experimentally proven.[provided by RefSeq, May 2010]

MANE transcript

NM_000338.3

Inheritance

ClinVar variants

P:152U:357B:276

Top phenotype

Bartter syndrome, antenatal, type 1

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr15:48,178,438-48,304,078

External References & Databases

Ensembl (ENSG00000074803)

Transcript & Mutation Effects

hg38 • Region Span ~125.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

antenatal Bartter syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100343

Submitter: ClinGen

The relationship between SLC12A1 (Solute carrier family 12, member1, Na-K-Cl transporter 2, previously known as NKCC2) and antenatal Bartter syndrome was evaluated using the ClinGen Clinical Validity Framework. The SLC12A1 gene encodes a Na-K-Cl transporter protein that mediates Na and Cl reabsorption, accounts for most NaCl reabsorption and has a key role in concentrating urine. SLC12A1 was first reported in relation to antenatal Bartter syndrome by Simon in 1996 PMID:8640224. Antenatal Bartter syndrome is the only disease associated with pathogenic variants in this gene. Many variants have been reported in SLC12A1 including nonsense and missense variants in many publications and public databases. The maximum score for genetic evidence was reached. The mechanism of pathogenicity is Loss of Function. This gene-disease association is also supported by experimental expression, biochemical function, functional alteration in non-patient cells and in a non-human model organism. In summary, SLC12A1 is definitively associated with Antenatal Bartter syndrome. This has been demonstrated in both the clinical diagnostic and research setting, and has been upheld over time. This assessment was performed according to the ClinGen Gene Clinical Validity SOP version 8 and was approved by the Tubulopathy Working Group on 21 April 2022.

Bartter disease type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100344

Submitter: PanelApp Australia

Bartter disease type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100344

Submitter: Labcorp Genetics (formerly Invitae)

Bartter disease type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100344

Submitter: Natera

Clinical Genomic Database (CGD)

Bartter syndrome, antenatal, type 1AR

Manifestation: Renal

Intervention: Renal

Rationale: Sequelae can be lethal; Medical treatment of manifestations including hypokalemia and metabolic alkalosis (eg, with KCl supplementation, NSAIDs), as well as related findings such as nephrocalcinosis, can be beneficial

Refs: 3863906; 8457138; 3888887; 8640224; 9355073; 19513753; 20219833

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC12A1 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 766

Bartter disease type 1Total: 319

Inborn genetic diseasesTotal: 136

SLC12A1-related disorderTotal: 65

not specifiedTotal: 54

Bartter syndromeTotal: 15

Kidney stoneTotal: 3

NephrocalcinosisTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000338.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	251 clinvar	1 clinvar	258
missense	1 clinvar	28 clinvar	340 clinvar	23 clinvar	1 clinvar	393
nonsense	26 clinvar	12 clinvar	4 clinvar			42
start loss						0
frameshift	26 clinvar	21 clinvar	3 clinvar			50
splice donor/acceptor (+/-2bp)	4 clinvar	34 clinvar	4 clinvar			42
Total	57	95	357	274	2	785

Highest pathogenic variant AF is 0.000052761603

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000338.3	RefSeq	NP_000329.2	26	MANE Select
ENST00000380993.8	Ensembl	ENSP00000370381.3	26	MANE Select
NM_001184832.2	RefSeq	NP_001171761.1	26	Standard
NM_001384136.1	RefSeq	NP_001371065.1	26	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Diuretics Pathway, Pharmacodynamics
Polythiazide Action Pathway
Methyclothiazide Action Pathway
Bumetanide Action Pathway
Spironolactone Action Pathway

Biological Process

ion transport
cell volume homeostasis
ion transmembrane transport
sodium ion transmembrane transport
chloride ion homeostasis

Molecular Function

sodium:potassium:chloride symporter activity
sodium ion transmembrane transporter activity
sodium:chloride symporter activity
potassium:chloride symporter activity

Cellular Component

plasma membrane
membrane
integral component of membrane
apical plasma membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396577
Coding exons: 26
Length: 112415
Individuals with no LoFs: 125465
Homozygous LoFs: 0
Heterozygous LoFs: 128
Defined: 125593
p: 0.000510

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.16	502	581	0.864	0.0000291	7188
Missense (PolyPhen)		212	269.91	0.78545		3340
Synonymous	-0.603	222	211	1.05	0.0000119	2076
Loss of Function	2.63	35	56.3	0.621	0.00000280	700

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00095	0.00095	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00044	0.00044	rare
Finnish	0.00046	0.00046	rare
European (Non-Finnish)	0.00046	0.00045	rare
South Asian	0.00047	0.00046	rare
Other	0.00083	0.00082	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Electrically silent transporter system. Mediates sodium and chloride reabsorption. Plays a vital role in the regulation of ionic balance and cell volume.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.0632
RVIS EVS: -0.83
RVIS percentile EVS: 11.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.171

Gene Damage Prediction

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