CLCN5
protein-codingchloride voltage-gated channel 5, the group of Chloride voltage-gated channels|MicroRNA protein coding host genes
Gene summary
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]
- NPHL2
- NPHL1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~176.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010225
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010225
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010225
Submitter: ClinGen
The *CLCN5* gene is located on chromosome X at p11.23 and encodes the chloride voltage-gated channel 5 protein, a chloride/proton exchanger primarily located in the endosomal membranes of proximal renal tubular cells. This protein is important for the acidification of early endosomes of proximal tubules and the re-absorption of low-molecular-weight proteins in the proximal tubule Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanism, inheritance pattern and phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity: Dent disease 1 (OMIM:300009), hypophosphatemic rickets (OMIM:300554), nephrolithiasis, type 1 (OMIM:310468) and proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis (OMIM:308990). The preferred disease name suggested for this grouping of disorders is ‘Dent disease - *CLCN5*’. *CLCN5* was first reported in relation to X-linked recessive Dent disease 1 in 1994 (Fisher et al., PMID: 7874126). The mechanism of pathogenicity is known to be loss of function. Dent disease 1 usually presents in childhood with low molecular weight proteinuria, hypercalciuria and additional features such as hypophosphatemia, nephrocalcinosis, nephrolithisasis, haematuria, renal insufficiency, bony deformities and short stature. At least 10 variants (7 nonsense, 1 canonical splice site, 2 missense) have been reported in 10 probands over 5 publications (PMIDs: 8559248, 30581818, 29084614, 9734595, 16822791 included in this curation). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data. This gene-disease relationship is also supported by expression studies and animal models. CIC-5 was shown to co-localise with the proton pump and endocytosed beta2-macroglobulin in the proximal tubule of rat kidney cells and the intercalating cells of the collecting duct (PMID: 9653142). Hemizygous *clcn5* knockout mice models recapitulated the human disease phenotype (PMIDs: 11099045, 15942052). A total of 4.5/6 pts. for experimental evidence was reached. In summary, there is definitive evidence supporting the relationship between *CLCN5* and X-linked recessive Dent Disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: XL
Disease ID:MONDO:0010225
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XLR
Disease ID:MONDO:0010225
Submitter: Natera
Clinical Genomic Database (CGD)
Manifestation: Endocrine; Renal
Intervention: Endocrine; Pharmacogenomic; Renal
Rationale: In Dent disease, surveillance and treatment related to manifestations such as hypercalciuria in order to prevent kidney stones, nephrocalcinosis, and to delay the progression of kidney dysfunction may be beneficial (though efficacy is unclear, treatment may include thiazide diuretics, ACE inhibitors, and ARBs); Vitamin D and phosphorous may be beneficial related to skeletal manifestations; Growth hormone may be indicated; Nephrotoxic agents (eg, NSAIDs, aminoglycosides) should be avoided
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CLCN5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001127898.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 24 | 63 | 6 | 94 | |
| missense | 14 | 27 | 236 | 25 | 1 | 303 |
| nonsense | 18 | 19 | 8 | 45 | ||
| start loss | 1 | 1 | ||||
| frameshift | 33 | 23 | 56 | |||
| splice donor/acceptor (+/-2bp) | 12 | 17 | 12 | 41 | ||
| Total | 77 | 87 | 281 | 88 | 7 | 540 |
Highest pathogenic variant AF is 0.000008942784
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001121370.1 | 13 | MANE Select | |
| Ensembl | ENSP00000365259.3 | 13 | MANE Select | |
| RefSeq | NP_000075.1 | 11 | Standard | |
| RefSeq | NP_001121371.1 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Stimuli-sensing channels
- Ion channel transport
- Transport of small molecules
Biological Process
- excretion
- ion transmembrane transport
- chloride transmembrane transport
- proton transmembrane transport
Molecular Function
- voltage-gated chloride channel activity
- chloride channel activity
- protein binding
- ATP binding
- antiporter activity
Cellular Component
- Golgi membrane
- lysosomal membrane
- endosome
- early endosome
- Golgi apparatus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000376088
- Coding exons
- 13
- Length
- 176668
- Individuals with no LoFs
- 125652
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 93
- Defined
- 125746
- p
- 0.000374
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.53 | 195 | 323 | 0.603 | 0.0000249 | 5349 |
| Missense (PolyPhen) | 66 | 150.78 | 0.43772 | 2479 | ||
| Synonymous | 1.59 | 94 | 116 | 0.812 | 0.00000865 | 1626 |
| Loss of Function | 4.36 | 3 | 27.8 | 0.108 | 0.00000235 | 422 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0040 | 0.0030 | notable |
| Latino/Admixed American | 0.000037 | 0.000029 | rare |
| Ashkenazi Jewish | 0.00027 | 0.00020 | rare |
| East Asian | 0.000072 | 0.000054 | rare |
| Finnish | 0.00069 | 0.00051 | rare |
| European (Non-Finnish) | 0.00036 | 0.00025 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00022 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- 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.;
- Disease
- DISEASE: Hypophosphatemic rickets, X-linked recessive (XLRHR) [MIM:300554]: 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. {ECO:0000269|PubMed:21305656, ECO:0000269|PubMed:8559248}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Nephrolithiasis 2 (NPHL2) [MIM:300009]: An X-linked recessive 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. Nephrolithiasis type 2 patients manifest hypercalciuria, hypophosphatemia, aminoaciduria, nephrocalcinosis and nephrolithiasis, renal insufficiency leading to renal failure in adulthood, rickets (33% of patients) and osteomalacia. {ECO:0000269|PubMed:15086899, ECO:0000269|PubMed:16247550, ECO:0000269|PubMed:16416111, ECO:0000269|PubMed:16822791, ECO:0000269|PubMed:17262170, ECO:0000269|PubMed:18025833, ECO:0000269|PubMed:19019917, ECO:0000269|PubMed:19657328, ECO:0000269|PubMed:21305656, ECO:0000269|PubMed:8559248, ECO:0000269|PubMed:9187673, ECO:0000269|PubMed:9259268, ECO:0000269|PubMed:9602200, ECO:0000269|PubMed:9853249}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Nephrolithiasis 1 (NPHL1) [MIM:310468]: An X-linked recessive 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. Nephrolithiasis type 1 presents with hypercalciuria, nephrocalcinosis, renal stones and renal insufficiency. Patients lack urinary acidification defects, rickets, and osteomalacia. {ECO:0000269|PubMed:8559248}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Low molecular weight proteinuria with hypercalciuria and nephrocalcinosis (LMWPHN) [MIM:308990]: An X-linked 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. LMWPHN is a slowly progressive disorder. Patients tend to have hypercalciuric nephrocalcinosis without rickets or renal failure. {ECO:0000269|PubMed:11136179, ECO:0000269|PubMed:19019917, ECO:0000269|PubMed:9062355}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.457
Intolerance Scores
- LoFtool
- 0.0134
- RVIS EVS
- 0.02
- RVIS percentile EVS
- 55.45
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.307
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |