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

    Gene ID: 1181, updated on 11-Apr-2024

    Summary

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    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

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    Location:
    3q27.1
    Exon count:
    25
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 3 NC_000003.12 (184346185..184361605, complement)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 3 NC_060927.1 (187155451..187170873, complement)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 3 NC_000003.11 (184063973..184079393, complement)

    Chromosome 3 - NC_000003.12Genomic Context describing neighboring genes Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14959 Neighboring gene proteasome 26S subunit ubiquitin receptor, non-ATPase 2 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:184031817-184032317 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:184033042-184033663 Neighboring gene eukaryotic translation initiation factor 4 gamma 1 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:184045141-184045641 Neighboring gene small nucleolar RNA, C/D box 66 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20908 Neighboring gene ReSE screen-validated silencer GRCh37_chr3:184053938-184054138 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:184055930-184056541 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20909 Neighboring gene family with sequence similarity 131 member A Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:184061884-184062636 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:184062637-184063388 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:184063389-184064141 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:184064142-184064893 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:184077025-184077538 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:184077539-184078050 Neighboring gene uncharacterized LOC124906311 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14964 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14965 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14966 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14967 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20910 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20911 Neighboring gene RNA polymerase II, I and III subunit H Neighboring gene thrombopoietin

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • 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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    Related articles in PubMed

    1. Biallelic CLCN2 mutations cause retinal degeneration by impairing retinal pigment epithelium phagocytosis and chloride channel function. Xu P, et al. Hum Genet, 2023 Apr. PMID 36964785
    2. Can Unlikely Neanderthal Chloride Channel CLC-2 Gene Variants Provide Insights in Modern Human Infertility? Jeworutzki E, et al. Cell Physiol Biochem, 2021 Jun 19. PMID 34148308
    3. Functional Analysis and Clinical Significance of Chloride Channel 2 Expression in Esophageal Squamous Cell Carcinoma. Mitsuda M, et al. Ann Surg Oncol, 2021 Sep. PMID 33565032
    4. A Novel Loss-of-Function Variant in the Chloride Ion Channel Gene Clcn2 Associates with Atrial Fibrillation. Hansen TH, et al. Sci Rep, 2020 Jan 29. PMID 31996765, Free PMC Article
    5. ClC-2 knockdown prevents cerebrovascular remodeling via inhibition of the Wnt/β-catenin signaling pathway. Lu J, et al. Cell Mol Biol Lett, 2018. PMID 29988306, Free PMC Article

    See all (65) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. 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.
    2. 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.
    3. 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.
    4. 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?
    5. 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.
    6. 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.
    7. 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.
    8. 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.
    9. 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.
    10. 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

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    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 
    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 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 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 retina development in camera-type eye IEA
    Inferred from Electronic Annotation
    more info
    		  
    Component Evidence Code Pubs
    part_of chloride channel complex IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in dendrite IEA
    Inferred from Electronic Annotation
    more info
    		  
    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
    		  

    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

    1. NG_016422.1 RefSeqGene

      Range
      4999..20419
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. 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

    2. 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

    3. 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

    4. 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_2023_10

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

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000003.12 Reference GRCh38.p14 Primary Assembly

      Range
      184346185..184361605 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. 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

    2. 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

    3. XM_047447419.1 → XP_047303375.1  chloride channel protein 2 isoform X3

      Related
      ENSP00000490313.1, ENST00000636492.1

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060927.1 Alternate T2T-CHM13v2.0

      Range
      187155451..187170873 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054345165.1 → XP_054201140.1  chloride channel protein 2 isoform X1

    2. XM_054345166.1 → XP_054201141.1  chloride channel protein 2 isoform X2

    3. XM_054345167.1 → XP_054201142.1  chloride channel protein 2 isoform X3

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    P51788.2 GenPept UniProtKB/Swiss-Prot:P51788

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