CLCN2 chloride voltage-gated channel 2 [Homo sapiens (human)] - Gene

Summary

Official Symbol: CLCN2provided by HGNC
Official Full Name: chloride voltage-gated channel 2provided by HGNC
Primary source: HGNC:HGNC:2020
See related: Ensembl:ENSG00000114859 MIM:600570; AllianceGenome:HGNC:2020
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: CLC2; ECA2; ECA3; EGI3; EGMA; EJM6; EJM8; FHA2; FHII; CIC-2; EGI11; HALD2; LKPAT; clC-2
Summary: This gene encodes a voltage-gated chloride channel. The encoded protein is a transmembrane protein that maintains chloride ion homeostasis in various cells. Defects in this gene may be a cause of certain epilepsies. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]
Expression: Broad expression in testis (RPKM 8.7), colon (RPKM 7.2) and 24 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 3q27.1

Exon count:: 25

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	3	NC_000003.12 (184346185..184361605, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	3	NC_060927.1 (187155451..187170873, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	3	NC_000003.11 (184063973..184079393, complement)

Chromosome 3 - NC_000003.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Biallelic CLCN2 mutations cause retinal degeneration by impairing retinal pigment epithelium phagocytosis and chloride channel function.
Title: Biallelic CLCN2 mutations cause retinal degeneration by impairing retinal pigment epithelium phagocytosis and chloride channel function.
FHII is linked to the chromosome 7p22 region but also shows predicted heterogeneity.
Title: Familial hyperaldosteronism type II is linked to the chromosome 7p22 region but also shows predicted heterogeneity.
Functional Analysis and Clinical Significance of Chloride Channel 2 Expression in Esophageal Squamous Cell Carcinoma.
Title: Functional Analysis and Clinical Significance of Chloride Channel 2 Expression in Esophageal Squamous Cell Carcinoma.
Can Unlikely Neanderthal Chloride Channel CLC-2 Gene Variants Provide Insights in Modern Human Infertility?
Title: Can Unlikely Neanderthal Chloride Channel CLC-2 Gene Variants Provide Insights in Modern Human Infertility?
Regulation of ClC-2 Chloride Channel Proteostasis by Molecular Chaperones: Correction of Leukodystrophy-Associated Defect.
Title: Regulation of ClC-2 Chloride Channel Proteostasis by Molecular Chaperones: Correction of Leukodystrophy-Associated Defect.
CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy.
Title: CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy.
this study shows possible link between loss of ClC-2 function and an increased risk of developing atrial fibrillation
Title: A Novel Loss-of-Function Variant in the Chloride Ion Channel Gene Clcn2 Associates with Atrial Fibrillation.
Three de novo epilepsy-related gene missense mutations were identified in SCN1A, SCN8A and CLCN2 in childhood absence epilepsy patients.
Title: De novo SCN1A, SCN8A, and CLCN2 mutations in childhood absence epilepsy.
CLCN2 mutations cause primary aldosteronism, this highlight the importance of chloride in aldosterone biosynthesis and CLCN2 as the foremost chloride conductor of resting glomerulosa cells.
Title: A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.
A role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. The mutations are the cause of a substantial fraction of early-onset primary aldosteronism.
Title: CLCN2 chloride channel mutations in familial hyperaldosteronism type II.

Submit: New GeneRIF Correction See all GeneRIFs (50)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Epilepsy, idiopathic generalized, susceptibility to, 11 MedGen: C2750893 OMIM: 607628 GeneReviews: Not available	not available
Familial hyperaldosteronism type II MedGen: C1854107 OMIM: 605635 GeneReviews: Not available	not available
Leukoencephalopathy with mild cerebellar ataxia and white matter edema MedGen: C4554120 OMIM: 615651 GeneReviews: CLCN2-Related Leukoencephalopathy	not available

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

SHGC-77635 (e-PCR)
- UniSTS:62009

D3S3725 (e-PCR), detects polymorphism
- UniSTS:73565

HSC2IC072 (e-PCR)
- UniSTS:28806

WI-11757 (e-PCR)
- UniSTS:81040

D3S1682 (e-PCR)
- UniSTS:154320

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables chloride channel regulator activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables voltage-gated chloride channel activity	IBA Inferred from Biological aspect of Ancestor more info
enables voltage-gated chloride channel activity	IDA Inferred from Direct Assay more info	PubMed
enables volume-sensitive chloride channel activity	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
involved_in acinar cell differentiation	IEA Inferred from Electronic Annotation more info
involved_in cell differentiation involved in salivary gland development	IEA Inferred from Electronic Annotation more info
involved_in cellular hypotonic response	IEA Inferred from Electronic Annotation more info
involved_in chloride transmembrane transport	IEA Inferred from Electronic Annotation more info
involved_in chloride transport	IBA Inferred from Biological aspect of Ancestor more info
involved_in lung development	IEA Inferred from Electronic Annotation more info
involved_in phagocytosis, engulfment	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of oligodendrocyte differentiation	IEA Inferred from Electronic Annotation more info
involved_in regulation of aldosterone biosynthetic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of membrane depolarization during action potential	IEA Inferred from Electronic Annotation more info
involved_in regulation of resting membrane potential	IEA Inferred from Electronic Annotation more info
involved_in retina development in camera-type eye	IEA Inferred from Electronic Annotation more info
involved_in stabilization of membrane potential	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
located_in astrocyte end-foot	IDA Inferred from Direct Assay more info	PubMed
located_in axon initial segment	IEA Inferred from Electronic Annotation more info
located_in basolateral plasma membrane	IDA Inferred from Direct Assay more info	PubMed
part_of chloride channel complex	IEA Inferred from Electronic Annotation more info
located_in dendritic spine membrane	IEA Inferred from Electronic Annotation more info
located_in myelin sheath	IDA Inferred from Direct Assay more info	PubMed
located_in perikaryon	IEA Inferred from Electronic Annotation more info
is_active_in plasma membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in plasma membrane	IDA Inferred from Direct Assay more info	PubMed
located_in plasma membrane	TAS Traceable Author Statement more info
located_in postsynaptic membrane	IEA Inferred from Electronic Annotation more info

General protein information

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Preferred Names: chloride channel protein 2

Names: chloride channel 2; chloride channel, voltage-sensitive 2

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_016422.1 RefSeqGene

Range

4999..20419

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001171087.3 → NP_001164558.1 chloride channel protein 2 isoform 2

See identical proteins and their annotated locations for NP_001164558.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) uses an alternate in-frame splice junction at the 5' end of an exon compared to variant 1. The resulting isoform (2) has the same N- and C-termini but is shorter compared to isoform 1.

Source sequence(s)

AA524434, BC072004, DC403930

Consensus CDS

CCDS54691.1

UniProtKB/Swiss-Prot

P51788

Related

ENSP00000345056.7, ENST00000344937.11

Conserved Domains (3) summary

cd03683
Location:90 → 550

ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...

cd04591
Location:773 → 821

CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...

pfam00654
Location:143 → 529

Voltage_CLC; Voltage gated chloride channel
NM_001171088.3 → NP_001164559.1 chloride channel protein 2 isoform 3

Status: REVIEWED

Description

Transcript Variant: This variant (3) lacks an alternate in-frame exon compared to variant 1. The resulting isoform (3) has the same N- and C-termini but is shorter compared to isoform 1.

Source sequence(s)

AA524434, AC078797, AK302759, DC403930

Consensus CDS

CCDS54690.1

UniProtKB/Swiss-Prot

P51788

Related

ENSP00000400425.2, ENST00000434054.6

Conserved Domains (3) summary

cd03683
Location:73 → 523

ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...

cd04591
Location:746 → 794

CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...

pfam00654
Location:99 → 502

Voltage_CLC; Voltage gated chloride channel
NM_001171089.3 → NP_001164560.1 chloride channel protein 2 isoform 4

Status: REVIEWED

Description

Transcript Variant: This variant (4) lacks an alternate in-frame exon compared to variant 1. The resulting isoform (4) has the same N- and C-termini but is shorter compared to isoform 1.

Source sequence(s)

AA524434, AC078797, AK298952, DC403930

Consensus CDS

CCDS54692.1

UniProtKB/Swiss-Prot

P51788

Related

ENSP00000391928.1, ENST00000457512.1

Conserved Domains (2) summary

cd03683
Location:90 → 567

ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...

pfam00654
Location:143 → 546

Voltage_CLC; Voltage gated chloride channel
NM_004366.6 → NP_004357.3 chloride channel protein 2 isoform 1

See identical proteins and their annotated locations for NP_004357.3

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1).

Source sequence(s)

AA524434, AC078797, AF026004, DC403930

Consensus CDS

CCDS3263.1

UniProtKB/Swiss-Prot

B4DQT9, B4DZ58, E9PBD9, E9PCD2, O14864, P51788, Q6IPA9, Q8WU13

Related

ENSP00000265593.4, ENST00000265593.9

Conserved Domains (3) summary

cd03683
Location:90 → 567

ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...

cd04591
Location:790 → 838

CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...

pfam00654
Location:143 → 546

Voltage_CLC; Voltage gated chloride channel

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000003.12 Reference GRCh38.p14 Primary Assembly

Range

184346185..184361605 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_006713489.2 → XP_006713552.1 chloride channel protein 2 isoform X1

See identical proteins and their annotated locations for XP_006713552.1

Conserved Domains (3) summary

cd03683
Location:90 → 567

ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...

cd04591
Location:762 → 803

CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...

pfam00654
Location:143 → 546

Voltage_CLC; Voltage gated chloride channel
XM_011512401.2 → XP_011510703.1 chloride channel protein 2 isoform X2

Conserved Domains (2) summary

cd03683
Location:90 → 567

ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...

pfam00654
Location:143 → 546

Voltage_CLC; Voltage gated chloride channel
XM_047447419.1 → XP_047303375.1 chloride channel protein 2 isoform X3

Related

ENSP00000490313.1, ENST00000636492.1