CLCNKB

protein-coding

chloride voltage-gated channel Kb, the group of Chloride voltage-gated channels

Gene summary

The protein encoded by this gene is a member of the family of voltage-gated chloride channels. Chloride channels have several functions, including the regulation of cell volume, membrane potential stabilization, signal transduction and transepithelial transport. This gene is expressed predominantly in the kidney and may be important for renal salt reabsorption. Mutations in this gene are associated with autosomal recessive Bartter syndrome type 3 (BS3). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

MANE transcript

NM_000085.5

Inheritance

AR, Digenic

ClinVar variants

P:94U:233B:140

Top phenotype

Bartter syndrome, type 3; Bartter syndrome, type 4, digenic

gnomAD constraint

pLI —, LoF o/e 0.93

Max pathogenic AF

—

Genomic locus

chr1:16,040,252-16,057,311

External References & Databases

Ensembl (ENSG00000184908)

Transcript & Mutation Effects

hg38 • Region Span ~17.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bartter disease type 4BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0000909

Submitter: G2P

Bartter disease type 4BDEFINITIVE

Inheritance Pattern: Digenic

Disease ID:MONDO:0000909

Submitter: Natera

Bartter disease type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011822

Submitter: Natera

Bartter disease type 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011822

Submitter: Orphanet

Bartter disease type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011822

Submitter: Labcorp Genetics (formerly Invitae)

Gitelman syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009904

Submitter: Orphanet

Bartter syndrome type 4SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019524

Submitter: Orphanet

Clinical Genomic Database (CGD)

Bartter syndrome, type 3; Bartter syndrome, type 4, digenicAR/Digenic

Manifestation: Audiologic/Otolaryngologic; Renal

Intervention: Audiologic/Otolaryngologic; Renal

Rationale: Due to renal salt wasting, individuals can present with dehydration and life-threatening hypotension, and electrolyte management can be beneficial; In some forms, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: Digenic inheritance (with CLCNKA) has been described

Refs: 13969763; 9326936; 11102542; 15044642; 18310267; 21162973; 20931281; 19807735; 21479528; 21631963

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLCNKB variants in ClinVar

17 Conditions Cataloged

not providedTotal: 405

Bartter disease type 3Total: 204

Bartter disease type 4BTotal: 174

Inborn genetic diseasesTotal: 98

not specifiedTotal: 62

CLCNKB-related disordersTotal: 17

Bartter syndromeTotal: 7

Renal tubulopathiesTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000085.5. 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		1 clinvar	8 clinvar	103 clinvar	2 clinvar	114
missense	5 clinvar	24 clinvar	220 clinvar	28 clinvar	7 clinvar	284
nonsense	10 clinvar	6 clinvar				16
start loss						0
frameshift	15 clinvar	16 clinvar				31
splice donor/acceptor (+/-2bp)	6 clinvar	11 clinvar	5 clinvar			22
Total	36	58	233	131	9	467

Highest pathogenic variant AF is 0.00078295014

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000085.5	RefSeq	NP_000076.2	19	MANE Select
ENST00000375679.9	Ensembl	ENSP00000364831.5	19	MANE Select
NM_001165945.2	RefSeq	NP_001159417.2	13	Standard
ENST00000375667.7	Ensembl	ENSP00000364819.3	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Collecting duct acid secretion - Homo sapiens (human)
Diuretics Pathway, Pharmacodynamics
Stimuli-sensing channels
Ion channel transport
Transport of small molecules

Biological Process

excretion
ion transmembrane transport
regulation of ion transmembrane transport
chloride transmembrane transport

Molecular Function

voltage-gated chloride channel activity
metal ion binding

Cellular Component

plasma membrane
integral component of plasma membrane
chloride channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375679
Coding exons: 19
Length: 13532
Individuals with no LoFs: 125552
Homozygous LoFs: 0
Heterozygous LoFs: 196
Defined: 125748
p: 0.000780

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.563	432	400	1.08	0.0000240	4414
Missense (PolyPhen)		123	128.6	0.95649		1453
Synonymous	-2.16	200	165	1.21	0.0000105	1424
Loss of Function	0.370	35	37.4	0.935	0.00000206	379

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00081	0.00080	rare
Latino/Admixed American	0.00081	0.00078	rare
Ashkenazi Jewish	0.0048	0.0048	notable
East Asian	0.00061	0.00060	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00072	0.00070	rare
South Asian	0.00027	0.00026	rare
Other	0.0012	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume; membrane potential stabilization, signal transduction and transepithelial transport. May be important in urinary concentrating mechanisms. {ECO:0000269|PubMed:11734858}.;
Disease: DISEASE: Bartter syndrome 4B, neonatal, with sensorineural deafness (BARTS4B) [MIM:613090]: A digenic form of Bartter syndrome, an autosomal recessive disorder characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and varying degrees of hypercalciuria. BARTS4B is associated with sensorineural deafness. {ECO:0000269|PubMed:15044642, ECO:0000269|PubMed:18310267}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Loss-of-function of both CLCNKA and CLCNKB results in the disease phenotype (PubMed:18310267). {ECO:0000269|PubMed:18310267}.;

Recessive Scores

pRec: 0.300

Intolerance Scores

LoFtool: 0.120
RVIS EVS: 0.7
RVIS percentile EVS: 85.3

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.180

Gene Damage Prediction

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