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 (23 variants)
• Dent disease type 1 (15 variants)
• Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis (2 variants)
• Inborn genetic diseases (2 variants)
• Hypophosphatemic rickets, X-linked recessive;X-linked recessive nephrolithiasis with renal failure;Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis;Dent disease type 1 (1 variants)
• CLCN5-related disorder (1 variants)
• Dent disease (1 variants)
• X-linked recessive nephrolithiasis with renal failure;Hypophosphatemic rickets, X-linked recessive;Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis;Dent disease type 1 (1 variants)
• Hypophosphatemic rickets, X-linked recessive (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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	36	8	46
missense	1	10	106	8	2	127
nonsense	12	9				21
start loss			1			1
frameshift	17	8				25
inframe indel	1		1			2
splice donor/acceptor (+/-2bp)	3	6	1			10
splice region		1	3	7	2	13
non coding			61	27	28	116
Total	34	33	172	71	38

Highest pathogenic variant AF is 0.00000894

Variants in CLCN5

This is a list of pathogenic ClinVar variants found in the CLCN5 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-49925299-A-G		Dent disease type 1	Uncertain significance (May 06, 2021)
X-50042261-G-A			Likely benign (Nov 10, 2018)
X-50042394-A-G		CLCN5-related disorder	Benign (Dec 11, 2019)
X-50042407-C-T			Benign (Sep 18, 2018)
X-50042451-G-A		Dent disease type 1 • Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis • Hypophosphatemic rickets, X-linked recessive • X-linked recessive nephrolithiasis with renal failure	Uncertain significance (-)
X-50067546-T-G		Dent disease	Likely benign (Jun 14, 2016)
X-50067578-G-A		Dent disease	Likely benign (Jun 14, 2016)
X-50067603-G-A		Dent disease type 1	Uncertain significance (Jan 13, 2018)
X-50067630-C-T		Dent disease type 1	Uncertain significance (Jan 13, 2018)
X-50067749-C-T		Dent disease type 1	Uncertain significance (Jan 13, 2018)
X-50067761-G-T		Dent disease type 1	Uncertain significance (Mar 28, 2023)
X-50069627-C-G			Benign (Sep 18, 2018)
X-50069947-A-G			Likely benign (Jun 13, 2022)
X-50069988-T-C			Likely benign (Jul 01, 2022)
X-50070007-C-T		Dent disease type 1 • Hypophosphatemic rickets, X-linked recessive;Dent disease type 1;X-linked recessive nephrolithiasis with renal failure;Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis	Pathogenic/Likely pathogenic (Mar 29, 2024)
X-50070013-C-T			Uncertain significance (Mar 09, 2022)
X-50070014-G-A			Uncertain significance (May 23, 2023)
X-50070025-C-T		Dent disease type 1 • CLCN5-related disorder • Familial X-linked hypophosphatemic vitamin D refractory rickets	Pathogenic/Likely pathogenic (Dec 07, 2022)
X-50070030-G-A		Dent disease type 1	Likely pathogenic (Apr 21, 2022)
X-50070031-G-A			Likely pathogenic (Nov 30, 2021)
X-50070032-TA-T			Uncertain significance (Sep 21, 2022)
X-50070042-G-A		Dent disease type 1 • X-linked recessive nephrolithiasis with renal failure;Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis;Hypophosphatemic rickets, X-linked recessive;Dent disease type 1	Benign (Dec 01, 2023)
X-50070048-A-AC			Likely benign (Apr 27, 2023)
X-50070049-C-T			Likely benign (Jan 12, 2024)
X-50072195-G-T			Likely benign (Jun 06, 2019)

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