CLCN5

chloride voltage-gated channel 5, the group of Chloride voltage-gated channels|MicroRNA protein coding host genes

Basic information

Region (hg38): X:49922596-50099235

Previous symbols: [ "NPHL2", "NPHL1" ]

Links

ENSG00000171365

∙ NCBI:1184 ∙ OMIM:300008 ∙ HGNC:2023 ∙ Uniprot:P51795 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

Dent disease type 1 (Definitive), mode of inheritance: XL
Dent disease type 1 (Supportive), mode of inheritance: XL
Dent disease type 1 (Strong), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Dent disease 1; Hypophosphatemic rickets, X-linked recessive; Nephrolithiasis, X-linked recessive, with renal failure; Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis	XL	Endocrine; Pharmacogenomic; Renal	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	Endocrine; Renal	14169453; 1908057; 1372109; 7915957; 7922301; 8559248; 9328929; 9062355; 9328927; 9187673; 602200; 15086899; 19673950; 22876375

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CLCN5 gene.

not_provided (265 variants)
Dent_disease_type_1 (172 variants)
Proteinuria,_low_molecular_weight,_with_hypercalciuria_and_nephrocalcinosis (91 variants)
X-linked_recessive_nephrolithiasis_with_renal_failure (89 variants)
Hypophosphatemic_rickets,_X-linked_recessive (86 variants)
Inborn_genetic_diseases (45 variants)
CLCN5-related_disorder (19 variants)
not_specified (15 variants)
Dent_disease (6 variants)
Nephrotic_syndrome (2 variants)
Familial_X-linked_hypophosphatemic_vitamin_D_refractory_rickets (1 variants)
Multiple_small_medullary_renal_cysts (1 variants)
Hypophosphataemia,_X-linked (1 variants)
Hyperkalemia (1 variants)
Low-molecular-weight_proteinuria (1 variants)
Bethlem_myopathy_1A (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CLCN5 gene is commonly pathogenic or not. These statistics are base on transcript: NM_001127898.4. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	5 clinvar	47 clinvar	8 clinvar	61
missense	12 clinvar	21 clinvar	156 clinvar	23 clinvar	2 clinvar	214
nonsense	17 clinvar	19 clinvar	1 clinvar			37
start loss			1			1
frameshift	29 clinvar	17 clinvar				46
splice donor/acceptor (+/-2bp)	7 clinvar	12 clinvar	1 clinvar			20
Total	65	70	164	70	10

Highest pathogenic variant AF is 0.000008942784

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CLCN5	protein_coding	protein_coding	ENST00000376088	13	176668

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.992	0.00758	125652	1	93	125746	0.000374

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.53	195	323	0.603	0.0000249	5349
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00407	0.00306
Ashkenazi Jewish	0.000268	0.000198
East Asian	0.0000721	0.0000544
Finnish	0.000693	0.000508
European (Non-Finnish)	0.000359	0.000255
Middle Eastern	0.0000721	0.0000544
South Asian	0.00	0.00
Other	0.000221	0.000163

dbNSFP

Source: dbNSFP

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.;
Pathway: Stimuli-sensing channels;Ion channel transport;Transport of small molecules (Consensus)

Recessive Scores

pRec: 0.457

Intolerance Scores

loftool: 0.0134
rvis_EVS: 0.02
rvis_percentile_EVS: 55.45

Haploinsufficiency Scores

pHI: 0.517
hipred: Y
hipred_score: 0.728
ghis: 0.512

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: N
gene_indispensability_score: 0.307

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

Gene name: Clcn5
Phenotype: growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; normal phenotype; skeleton phenotype; renal/urinary system phenotype;

Gene ontology

Biological process: excretion;ion transmembrane transport;chloride transmembrane transport;proton transmembrane transport
Cellular component: Golgi membrane;lysosomal membrane;endosome;early endosome;Golgi apparatus;cytosol;plasma membrane;integral component of plasma membrane;endosome membrane;membrane;apical part of cell
Molecular function: voltage-gated chloride channel activity;chloride channel activity;protein binding;ATP binding;antiporter activity;solute:proton antiporter activity;chloride ion binding;identical protein binding