CLCNKA

protein-coding

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

Gene summary

This gene is a member of the CLC family of voltage-gated chloride channels. The encoded protein is predicted to have 12 transmembrane domains, and requires a beta subunit called barttin to form a functional channel. It is thought to function in salt reabsorption in the kidney and potassium recycling in the inner ear. The gene is highly similar to CLCNKB, which is located 10 kb downstream from this gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004070.4

Inheritance

AR, Digenic

ClinVar variants

P:7U:132B:61

Top phenotype

Bartter syndrome, type 4, digenic

gnomAD constraint

pLI —, LoF o/e 0.82

Max pathogenic AF

—

Genomic locus

chr1:16,018,875-16,034,050

External References & Databases

Ensembl (ENSG00000186510)

Transcript & Mutation Effects

hg38 • Region Span ~15.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bartter syndrome type 4SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019524

Submitter: Orphanet

Bartter disease type 4BLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0000909

Submitter: G2P

Bartter disease type 4BMODERATE

Inheritance Pattern: Unknown

Disease ID:MONDO:0000909

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

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 CLCNKB) has been described

Refs: 15044642; 18310267

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLCNKA variants in ClinVar

10 Conditions Cataloged

Inborn genetic diseasesTotal: 114

not providedTotal: 74

not specifiedTotal: 55

Bartter disease type 4BTotal: 20

Bartter syndrome type 4Total: 2

CHARGE syndromeTotal: 1

DeafnessTotal: 1

Bartter disease type 3Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004070.4. 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			3 clinvar	29 clinvar	4 clinvar	36
missense	1 clinvar	1 clinvar	123 clinvar	27 clinvar	1 clinvar	153
nonsense	1 clinvar	3 clinvar	1 clinvar			5
start loss						0
frameshift		1 clinvar	4 clinvar			5
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	2	5	132	56	5	200

Highest pathogenic variant AF is 0.00037962577

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004070.4	RefSeq	NP_004061.3	19	MANE Select
ENST00000331433.5	Ensembl	ENSP00000332771.4	19	MANE Select
NM_001042704.2	RefSeq	NP_001036169.1	19	Standard
NM_001257139.2	RefSeq	NP_001244068.1	18	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

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

Molecular Function

voltage-gated chloride channel activity
identical protein binding
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: ENST00000331433
Coding exons: 19
Length: 15176
Individuals with no LoFs: 125198
Homozygous LoFs: 0
Heterozygous LoFs: 550
Defined: 125748
p: 0.00219

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.334	406	387	1.05	0.0000235	4404
Missense (PolyPhen)		124	128.3	0.96647		1455
Synonymous	-2.53	210	168	1.25	0.0000114	1443
Loss of Function	1.00	29	35.4	0.818	0.00000179	383

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0087	0.0077	notable
Latino/Admixed American	0.0010	0.0010	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00093	0.00092	rare
Finnish	0.0013	0.0013	notable
European (Non-Finnish)	0.0028	0.0028	notable
South Asian	0.00046	0.00046	rare
Other	0.0023	0.0023	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.;

Recessive Scores

pRec: 0.192

Intolerance Scores

LoFtool: 0.0670
RVIS EVS: 1.54
RVIS percentile EVS: 95.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.147

Gene Damage Prediction

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