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; Vega:OTTHUMG00000156747
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; 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

Genomic context

Location:: 3q27.1

Exon count:: 25

Annotation release	Status	Assembly	Chr	Location
109	current	GRCh38.p12 (GCF_000001405.38)	3	NC_000003.12 (184346185..184361651, complement)
105	previous assembly	GRCh37.p13 (GCF_000001405.25)	3	NC_000003.11 (184063973..184079439, 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 Jun 15 11:32:44 2016

Bibliography

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GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

Leukoencephalopathy-causing CLCN2 mutations impair chloride channel gating and trafficking.
Title: Leukoencephalopathy-causing CLCN2 mutations are associated with impaired Cl<sup>-</sup> channel function and trafficking.
ClC-2 mRNA level was significantly increased in patients with non-alcoholic steatohepatitis, which positively correlated with the plasma levels of alanine transaminase (ALT), aspartate transaminase (AST) and insulin.
Title: Lack of ClC-2 Alleviates High Fat Diet-Induced Insulin Resistance and Non-Alcoholic Fatty Liver Disease.
The findings show that RGET691 of human ClC-2 (possible binding site) plays an important functional role in fatty acid activation of human ClC-2.
Title: Identification of the fatty acid activation site on human ClC-2.
Hyperpolarization activates CLC-2 mainly by driving intracellular anions into the channel pores.
Title: Gating the glutamate gate of CLC-2 chloride channel by pore occupancy.
The extracellular domain of GlialCAM is necessary for cell junction targeting and for mediating interactions with itself or with MLC1 and ClC-2.
Title: Structural determinants of interaction, trafficking and function in the ClC-2/MLC1 subunit GlialCAM involved in leukodystrophy.
both ubiquitous (AP-1A) and epithelium-specific (AP-1B) forms of the tetrameric clathrin adaptor AP-1 are capable of carrying out basolateral sorting of ClC-2.
Title: Basolateral sorting of chloride channel 2 is mediated by interactions between a dileucine motif and the clathrin adaptor AP-1.
SPAK and OSR1 are powerful negative regulators of the cell volume regulatory Cl- channel ClC-2
Title: Regulation of ClC-2 activity by SPAK and OSR1.
Correlation between CLC-2 gene expression and the cytoskeleton in human trabecular meshwork cells.
Title: Effect of CLC-2 on the cytoskeleton in human trabecular meshwork cells.
Our observations substantiate the concept that ClC-2 is involved in brain ion and water homoeostasis
Title: Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study.
JAK2 down-regulates ClC-2 activity and thus counteracts Cl(-) exit, an effect which may impact on cell volume regulation
Title: Downregulation of ClC-2 by JAK2.

Submit: New GeneRIF Correction See all GeneRIFs (39)

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 with grand mal seizures on awakening MedGen: C0393697 OMIM: 607628 GeneReviews: Not available	Compare labs
Hyperaldosteronism, familial, type II MedGen: C1854107 OMIM: 605635 GeneReviews: Not available	not available
Leukoencephalopathy with ataxia MedGen: C3810242 OMIM: 615651 GeneReviews: CLCN2-Related Leukoencephalopathy	Compare labs

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Pathways from BioSystems

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Ion channel transport, organism-specific biosystem (from REACTOME)
Ion channel transport, organism-specific biosystemIon channels mediate the flow of ions across the plasma membrane of cells. They are integral membrane proteins, typically a multimer of proteins, which, when arranged in the membrane, create a pore f...
Mineral absorption, organism-specific biosystem (from KEGG)
Mineral absorption, organism-specific biosystemMinerals are one of the five fundamental groups of nutrients needed to sustain life. Of the minerals, calcium plays innumerable roles in our bodies, serving as a main component of bone as well as an ...
Mineral absorption, conserved biosystem (from KEGG)
Mineral absorption, conserved biosystemMinerals are one of the five fundamental groups of nutrients needed to sustain life. Of the minerals, calcium plays innumerable roles in our bodies, serving as a main component of bone as well as an ...
Stimuli-sensing channels, organism-specific biosystem (from REACTOME)
Stimuli-sensing channels, organism-specific biosystemIon channels that mediate sensations such as pain, warmth, cold, taste pressure and vision. Channels that mediate these sensations include acid-sensing ion channels (ASICs) (Wang & Xu 2011, Qadri et ...
Transmembrane transport of small molecules, organism-specific biosystem (from REACTOME)
Transmembrane transport of small molecules, organism-specific biosystem
Transmembrane transport of small molecules

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

Homology

Homologs of the CLCN2 gene: The CLCN2 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito, C.elegans, and frog.
Orthologs from Annotation Pipeline: 212 organisms have orthologs with human gene CLCN2
The Hierarchical Catalog of Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
voltage-gated chloride channel activity	TAS Traceable Author Statement more info

Process	Evidence Code	Pubs
cell differentiation involved in salivary gland development	IEA Inferred from Electronic Annotation more info
chloride transmembrane transport	IEA Inferred from Electronic Annotation more info
ion transmembrane transport	TAS Traceable Author Statement more info
regulation of ion transmembrane transport	IEA Inferred from Electronic Annotation more info
retina development in camera-type eye	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
chloride channel complex	IEA Inferred from Electronic Annotation more info
integral component of plasma membrane	IBA Inferred from Biological aspect of Ancestor more info	PubMed
plasma membrane	TAS Traceable Author Statement 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

4953..20419

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001171087.2 → 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, OTTHUMP00000210516, ENST00000344937.11, OTTHUMT00000345574

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_001171088.2 → 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, OTTHUMP00000210515, ENST00000434054.6, OTTHUMT00000345573

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_001171089.2 → 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, OTTHUMP00000210514, ENST00000457512.1, OTTHUMT00000345572

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_004366.5 → 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

P51788

Related

ENSP00000265593.4, OTTHUMP00000210513, ENST00000265593.8, OTTHUMT00000345571

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: Homo sapiens Annotation Release 109 details...

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

Reference GRCh38.p12 Primary Assembly

Genomic

NC_000003.12 Reference GRCh38.p12 Primary Assembly

Range

184346185..184361651 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_006713489.1 → 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_006713490.2 → XP_006713553.1 chloride channel protein 2 isoform X3

Conserved Domains (3) summary

cd04591
Location:404 → 452

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:46 → 160

Voltage_CLC; Voltage gated chloride channel

cl02915
Location:46 → 181

Voltage_gated_ClC; CLC voltage-gated chloride channel. The ClC chloride channels catalyse the selective flow of Cl- ions across cell membranes, thereby regulating electrical excitation in skeletal muscle and the flow of salt and water across epithelial barriers. This ...
XM_011512401.1 → 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