CLCNKB

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

Basic information

Region (hg38): 1:16040251-16057311

Links

ENSG00000184908 ∙ NCBI:1188 ∙ OMIM:602023 ∙ HGNC:2027 ∙ Uniprot:P51801 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Gitelman syndrome (Supportive), mode of inheritance: AR
• Bartter syndrome type 4 (Supportive), mode of inheritance: AR
• Bartter disease type 3 (Supportive), mode of inheritance: AR
• Bartter disease type 3 (Strong), mode of inheritance: AR
• Bartter disease type 4B (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Bartter syndrome, type 3; Bartter syndrome, type 4, digenic	AR/Digenic	Audiologic/Otolaryngologic; Renal	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	Audiologic/Otolaryngologic; Renal	13969763; 9326936; 11102542; 15044642; 18310267; 21162973; 20931281; 19807735; 21479528; 21631963
Digenic inheritance (with CLCNKA) has been described

ClinVar

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

• not provided (379 variants)
• Bartter disease type 3 (52 variants)
• Bartter disease type 3;Bartter disease type 4B (37 variants)
• not specified (34 variants)
• Inborn genetic diseases (27 variants)
• Bartter disease type 4B (24 variants)
• Bartter disease type 4B;Bartter disease type 3 (13 variants)
• Hematuria;Proteinuria (2 variants)
• Bartter syndrome, type 3, with hypocalciuria (1 variants)
• Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant (1 variants)
• Bartter syndrome (1 variants)
• Epilepsy, familial focal, with variable foci 1 (1 variants)
• Autosomal dominant osteopetrosis 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CLCNKB 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			1	51	12	64
missense	5	6	89	13	14	127
nonsense	8	3				11
start loss						0
frameshift	9	3				12
inframe indel			3			3
splice donor/acceptor (+/-2bp)	3	2				5
splice region			2	8	4	14
non coding			1	44	116	161
Total	25	14	94	108	142

Highest pathogenic variant AF is 0.0000855

Variants in CLCNKB

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

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

Position	Type	Phenotype	Significance	ClinVar
1-16044169-T-G			Benign (Nov 10, 2018)
1-16044182-G-C			Benign (Nov 10, 2018)
1-16044217-T-C			Benign (Nov 10, 2018)
1-16044238-CAG-C			Benign (Nov 10, 2018)
1-16044246-C-T			Benign (Nov 10, 2018)
1-16044296-C-G			Benign (Nov 22, 2019)
1-16044378-C-CACACACACACACAT			Benign (Nov 26, 2019)
1-16044378-C-CACACACACAT			Benign (Aug 20, 2019)
1-16044378-C-CACACACACACAT			Likely benign (Nov 29, 2019)
1-16044404-G-A			Benign (Nov 10, 2018)
1-16044501-G-T		Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 14, 2023)
1-16044504-T-G		not specified	Benign (Jan 19, 2024)
1-16044506-T-TG		Bartter disease type 3 • Bartter disease type 3;Bartter disease type 4B	Pathogenic (Feb 23, 2022)
1-16044515-G-A		Bartter disease type 3;Bartter disease type 4B	Uncertain significance (Mar 10, 2022)
1-16044544-C-T		Bartter disease type 3;Bartter disease type 4B	Likely benign (May 05, 2023)
1-16044555-G-A			Likely benign (Oct 23, 2023)
1-16044563-C-T			Uncertain significance (-)
1-16044564-CT-C			Pathogenic (Apr 15, 2016)
1-16044570-C-A			Likely benign (Oct 24, 2023)
1-16044571-C-G		Inborn genetic diseases	Uncertain significance (Jan 23, 2024)
1-16044572-G-T		not specified • Bartter disease type 4B • Bartter disease type 3	Benign (Feb 01, 2024)
1-16044578-G-A			Uncertain significance (Feb 06, 2022)
1-16044590-G-A		Bartter disease type 4B;Bartter disease type 3	Uncertain significance (Apr 02, 2022)
1-16044607-C-G			Likely benign (Aug 21, 2022)
1-16044787-G-A			Likely benign (Jan 23, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CLCNKB	protein_coding	protein_coding	ENST00000375679	19	13532

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.40e-22	0.00242	125552	0	196	125748	0.000780

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.563	432	400	1.08	0.0000240	4414
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00162	0.00161
Ashkenazi Jewish	0.00480	0.00477
East Asian	0.000606	0.000598
Finnish	0.0000925	0.0000924
European (Non-Finnish)	0.000723	0.000703
Middle Eastern	0.000606	0.000598
South Asian	0.000266	0.000261
Other	0.00117	0.00114

dbNSFP

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

Recessive Scores

• pRec: 0.300

Intolerance Scores

• loftool: 0.120
• rvis_EVS: 0.7
• rvis_percentile_EVS: 85.3

Haploinsufficiency Scores

• pHI: 0.139
• hipred: N
• hipred_score: 0.112
• ghis: 0.388

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.180

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Clcnkb
• Phenotype: growth/size/body region phenotype; homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); 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); renal/urinary system phenotype

Gene ontology

• Biological process: excretion;ion transmembrane transport;regulation of ion transmembrane transport;chloride transmembrane transport
• Cellular component: plasma membrane;integral component of plasma membrane;chloride channel complex
• Molecular function: voltage-gated chloride channel activity;metal ion binding