Human Gene CLCN5 (ENST00000376088.7) from GENCODE V44
  Description: Homo sapiens chloride voltage-gated channel 5 (CLCN5), transcript variant 1, mRNA. (from RefSeq NM_001127899)
RefSeq Summary (NM_001127899): This gene encodes a member of the ClC family of chloride ion channels and ion transporters. The encoded protein is primarily localized to endosomal membranes and may function to facilitate albumin uptake by the renal proximal tubule. Mutations in this gene have been found in Dent disease and renal tubular disorders complicated by nephrolithiasis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013].
Gencode Transcript: ENST00000376088.7
Gencode Gene: ENSG00000171365.17
Transcript (Including UTRs)
   Position: hg38 chrX:49,922,615-50,099,235 Size: 176,621 Total Exon Count: 15 Strand: +
Coding Region
   Position: hg38 chrX:49,925,299-50,092,219 Size: 166,921 Coding Exon Count: 13 

Page IndexSequence and LinksUniProtKB CommentsPrimersMalaCardsCTD
RNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther SpeciesGO Annotations
mRNA DescriptionsPathwaysOther NamesGeneReviewsMethods
Data last updated at UCSC: 2023-08-18 09:09:47

-  Sequence and Links to Tools and Databases
Genomic Sequence (chrX:49,922,615-50,099,235)mRNA (may differ from genome)Protein (816 aa)
Gene SorterGenome BrowserOther Species FASTAGene interactionsTable SchemaAlphaFold
BioGPSEnsemblEntrez GeneExonPrimerGencodeGeneCards

-  Comments and Description Text from UniProtKB
DESCRIPTION: RecName: Full=H(+)/Cl(-) exchange transporter 5; AltName: Full=Chloride channel protein 5; Short=ClC-5; AltName: Full=Chloride transporter ClC-5;
FUNCTION: Proton-coupled chloride transporter. Functions as antiport system and exchanges chloride ions against protons. Important for normal acidification of the endosome lumen. May play an important role in renal tubular function.
SUBUNIT: Interacts with NEDD4 and NEDD4L.
SUBCELLULAR LOCATION: Golgi apparatus membrane; Multi-pass membrane protein. Endosome membrane; Multi-pass membrane protein. Cell membrane; Multi-pass membrane protein.
TISSUE SPECIFICITY: Kidney. Moderately expressed in aortic vascular smooth muscle and endothelial cells, and at a slightly higher level in the coronary vascular smooth muscle.
PTM: Ubiquitinated by NEDD4L in the presence of albumin; which promotes endocytosis and proteasomal degradation.
DISEASE: Defects in CLCN5 are a cause of hypophosphatemic rickets, X-linked recessive (XLRHR) [MIM:300554]. XLRHR is a renal disease belonging to the 'Dent disease complex', a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. XLRH patients present with rickets or osteomalacia, hypophosphatemia due to decreased renal tubular phosphate reabsorption, hypercalciuria, and low molecular weight proteinuria. Patients develop nephrocalcinosis with progressive renal failure in adulthood. Female carriers may have asymptomatic hypercalciuria or hypophosphatemia only.
DISEASE: Defects in CLCN5 are the cause of nephrolithiasis type 2 (NPHL2) [MIM:300009]; also known as Dent disease 1. NPHL2 is an X- linked recessive renal disease belonging to the 'Dent disease complex'. NPHL2 patients manifest hypercalciuria, hypophosphatemia, aminoaciduria, nephrocalcinosis and nephrolithiasis, renal insufficiency leading to renal failure in adulthood, rickets (33% of patients) and osteomalacia.
DISEASE: Defects in CLCN5 are the cause of nephrolithiasis type 1 (NPHL1) [MIM:310468]; also designated XRN. NPHL1 is an X-linked recessive renal disease belonging to the 'Dent disease complex'. NPHL1 presents with hypercalciuria, nephrocalcinosis, renal stones and renal insufficiency. Patients lack urinary acidification defects, rickets, and osteomalacia.
DISEASE: Defects in CLCN5 are the cause of low molecular weight proteinuria with hypercalciuria and nephrocalcinosis (LMWPHN) [MIM:308990]. LMWPHN is an X-linked renal disease belonging to the 'Dent disease complex'. Patients tend to have hypercalciuric nephrocalcinosis without rickets or renal failure.
MISCELLANEOUS: The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons. The absence of conserved gating glutamate residues is typical for family members that function as channels.
SIMILARITY: Belongs to the chloride channel (TC 2.A.49) family. ClC-5/CLCN5 subfamily.
SIMILARITY: Contains 2 CBS domains.
WEB RESOURCE: Name=GeneReviews; URL="";

-  Primer design for this transcript

Primer3Plus can design qPCR Primers that straddle exon-exon-junctions, which amplify only cDNA, not genomic DNA.
Click here to load the transcript sequence and exon structure into Primer3Plus

Exonprimer can design one pair of Sanger sequencing primers around every exon, located in non-genic sequence.
Click here to open Exonprimer with this transcript

To design primers for a non-coding sequence, zoom to a region of interest and select from the drop-down menu: View > In External Tools > Primer3

-  MalaCards Disease Associations
  MalaCards Gene Search: CLCN5
Diseases sorted by gene-association score: dent disease* (1724), hypophosphatemic rickets* (1348), proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis* (1300), nephrolithiasis, type i* (900), nephrolithiasis (58), nephrocalcinosis (42), rickets (23), renal tubular transport disease (19), aminoaciduria (16), fanconi syndrome (12), nephrolithiasis, calcium oxalate (11), lowe syndrome (10), hypercalciuria, absorptive (10), bartter disease (9), hypophosphatemia (8), mineral metabolism disease (5), idiopathic hypercalciuria (4)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 8.80 RPKM in Kidney - Cortex
Total median expression: 88.56 RPKM

View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -209.80641-0.327 Picture PostScript Text
3' UTR -1950.217016-0.278 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR014743 - Cl-channel_core
IPR001807 - Cl-channel_volt-gated
IPR002247 - Cl_channel-5
IPR000644 - Cysta_beta_synth_core

Pfam Domains:
PF00571 - CBS domain
PF00654 - Voltage gated chloride channel

Protein Data Bank (PDB) 3-D Structure
MuPIT help
2J9L - X-ray MuPIT 2JA3 - X-ray MuPIT

ModBase Predicted Comparative 3D Structure on P51795
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
Genome BrowserGenome BrowserGenome BrowserNo orthologNo orthologNo ortholog
Gene Details     
Gene Sorter     
Protein SequenceProtein SequenceProtein Sequence   

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0000166 nucleotide binding
GO:0005247 voltage-gated chloride channel activity
GO:0005254 chloride channel activity
GO:0005515 protein binding
GO:0005524 ATP binding
GO:0015297 antiporter activity
GO:0042802 identical protein binding

Biological Process:
GO:0006811 ion transport
GO:0006821 chloride transport
GO:0007588 excretion
GO:0034220 ion transmembrane transport
GO:0055085 transmembrane transport
GO:1902476 chloride transmembrane transport

Cellular Component:
GO:0000139 Golgi membrane
GO:0005765 lysosomal membrane
GO:0005768 endosome
GO:0005794 Golgi apparatus
GO:0005829 cytosol
GO:0005886 plasma membrane
GO:0005887 integral component of plasma membrane
GO:0010008 endosome membrane
GO:0016020 membrane
GO:0016021 integral component of membrane
GO:0045177 apical part of cell

-  Descriptions from all associated GenBank mRNAs
  AK092049 - Homo sapiens cDNA FLJ34730 fis, clone MESAN2006580, highly similar to Chloride channel protein 5.
AK056560 - Homo sapiens cDNA FLJ31998 fis, clone NT2RP7009322, highly similar to CHLORIDE CHANNEL PROTEIN 5.
AK308089 - Homo sapiens cDNA, FLJ98037.
AK290940 - Homo sapiens cDNA FLJ77943 complete cds, highly similar to Homo sapiens chloride channel 5 (nephrolithiasis 2, X-linked, Dent disease) (CLCN5), mRNA.
X91906 - H.sapiens voltage-gated chloride ion channel CLCN5.
BC130429 - Homo sapiens chloride channel 5, mRNA (cDNA clone MGC:163301 IMAGE:40146460), complete cds.
BC130431 - Homo sapiens chloride channel 5, mRNA (cDNA clone MGC:163303 IMAGE:40146462), complete cds.
HQ258649 - Synthetic construct Homo sapiens clone IMAGE:100072679 chloride channel 5 (CLCN5), transcript variant 3 (CLCN5) gene, encodes complete protein.
KJ890928 - Synthetic construct Homo sapiens clone ccsbBroadEn_00322 CLCN5 gene, encodes complete protein.
KR711698 - Synthetic construct Homo sapiens clone CCSBHm_00028578 CLCN5 (CLCN5) mRNA, encodes complete protein.
KR711699 - Synthetic construct Homo sapiens clone CCSBHm_00028583 CLCN5 (CLCN5) mRNA, encodes complete protein.
KR711700 - Synthetic construct Homo sapiens clone CCSBHm_00028614 CLCN5 (CLCN5) mRNA, encodes complete protein.
KR711701 - Synthetic construct Homo sapiens clone CCSBHm_00028630 CLCN5 (CLCN5) mRNA, encodes complete protein.
X81836 - H.sapiens mRNA for Dents Disease candidate gene.
JD363883 - Sequence 344907 from Patent EP1572962.
JD294306 - Sequence 275330 from Patent EP1572962.
JD507248 - Sequence 488272 from Patent EP1572962.
AK021494 - Homo sapiens cDNA FLJ11432 fis, clone HEMBA1001099.
JD040410 - Sequence 21434 from Patent EP1572962.
JD357810 - Sequence 338834 from Patent EP1572962.
JD150684 - Sequence 131708 from Patent EP1572962.
JD154465 - Sequence 135489 from Patent EP1572962.
BC051691 - Homo sapiens hypothetical protein LOC158563, mRNA (cDNA clone IMAGE:5314973).
JD454277 - Sequence 435301 from Patent EP1572962.
JD091079 - Sequence 72103 from Patent EP1572962.
JD434288 - Sequence 415312 from Patent EP1572962.
JD506461 - Sequence 487485 from Patent EP1572962.
JD061510 - Sequence 42534 from Patent EP1572962.
JD243430 - Sequence 224454 from Patent EP1572962.
JD566892 - Sequence 547916 from Patent EP1572962.
JD271858 - Sequence 252882 from Patent EP1572962.
JD465126 - Sequence 446150 from Patent EP1572962.
JD417969 - Sequence 398993 from Patent EP1572962.
JD524108 - Sequence 505132 from Patent EP1572962.
JD146782 - Sequence 127806 from Patent EP1572962.
JD510096 - Sequence 491120 from Patent EP1572962.
JD351179 - Sequence 332203 from Patent EP1572962.
JD407688 - Sequence 388712 from Patent EP1572962.
JD213435 - Sequence 194459 from Patent EP1572962.
JD160204 - Sequence 141228 from Patent EP1572962.
JD280015 - Sequence 261039 from Patent EP1572962.
JD396046 - Sequence 377070 from Patent EP1572962.
JD080220 - Sequence 61244 from Patent EP1572962.
JD344000 - Sequence 325024 from Patent EP1572962.
JD203764 - Sequence 184788 from Patent EP1572962.
JD505558 - Sequence 486582 from Patent EP1572962.
JD365013 - Sequence 346037 from Patent EP1572962.
JD365012 - Sequence 346036 from Patent EP1572962.
JD425273 - Sequence 406297 from Patent EP1572962.
JD131339 - Sequence 112363 from Patent EP1572962.
JD448379 - Sequence 429403 from Patent EP1572962.
JD053196 - Sequence 34220 from Patent EP1572962.
AK025562 - Homo sapiens cDNA: FLJ21909 fis, clone HEP03834.
JD188585 - Sequence 169609 from Patent EP1572962.
JD563880 - Sequence 544904 from Patent EP1572962.
JD326314 - Sequence 307338 from Patent EP1572962.
JD036564 - Sequence 17588 from Patent EP1572962.
JD448699 - Sequence 429723 from Patent EP1572962.
JD419472 - Sequence 400496 from Patent EP1572962.
JD261518 - Sequence 242542 from Patent EP1572962.
JD290331 - Sequence 271355 from Patent EP1572962.
JD257502 - Sequence 238526 from Patent EP1572962.
JD121967 - Sequence 102991 from Patent EP1572962.
JD431967 - Sequence 412991 from Patent EP1572962.
JD552765 - Sequence 533789 from Patent EP1572962.
JD432888 - Sequence 413912 from Patent EP1572962.
JD044092 - Sequence 25116 from Patent EP1572962.
JD422275 - Sequence 403299 from Patent EP1572962.
JD524354 - Sequence 505378 from Patent EP1572962.
JD170834 - Sequence 151858 from Patent EP1572962.
JD503585 - Sequence 484609 from Patent EP1572962.
JD493042 - Sequence 474066 from Patent EP1572962.
JD501275 - Sequence 482299 from Patent EP1572962.
JD137671 - Sequence 118695 from Patent EP1572962.
JD362878 - Sequence 343902 from Patent EP1572962.
JD202017 - Sequence 183041 from Patent EP1572962.
JD126560 - Sequence 107584 from Patent EP1572962.
JD504052 - Sequence 485076 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  Reactome (by CSHL, EBI, and GO)

Protein P51795 (Reactome details) participates in the following event(s):

R-HSA-2730692 CLCN4/5/6 exchange Cl- for H+
R-HSA-2672351 Stimuli-sensing channels
R-HSA-983712 Ion channel transport
R-HSA-382551 Transport of small molecules

-  Other Names for This Gene
  Alternate Gene Symbols: A1L475, B3KPN6, CLCK2, CLCN5_HUMAN, ENST00000376088.1, ENST00000376088.2, ENST00000376088.3, ENST00000376088.4, ENST00000376088.5, ENST00000376088.6, NM_001127899, P51795, Q5JQD5, Q7RTN8, uc004dor.1
UCSC ID: ENST00000376088.7
RefSeq Accession: NM_001127899
Protein: P51795 (aka CLCN5_HUMAN or CLC5_HUMAN)
CCDS: CCDS48115.1

-  GeneReviews for This Gene
  GeneReviews article(s) related to gene CLCN5:
dent (Dent Disease)

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.