CLCN3

chloride voltage-gated channel 3, the group of Chloride voltage-gated channels

Basic information

Region (hg38): 4:169612633-169723673

Links

ENSG00000109572 ∙ NCBI:1182 ∙ OMIM:600580 ∙ HGNC:2021 ∙ Uniprot:P51790 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurodevelopmental disorder with hypotonia and brain abnormalities (Moderate), mode of inheritance: AD
• neurodevelopmental disorder with seizures and brain abnormalities (Limited), mode of inheritance: AR
• complex neurodevelopmental disorder (Strong), mode of inheritance: AD
• neurodevelopmental disorder with hypotonia and brain abnormalities (Strong), mode of inheritance: AD
• neurodevelopmental disorder with seizures and brain abnormalities (Limited), mode of inheritance: AR
• neurodevelopmental disorder with seizures and brain abnormalities (Limited), mode of inheritance: AR
• neurodevelopmental disorder with hypotonia and brain abnormalities (Strong), mode of inheritance: AD
• neurodevelopmental disorder with hypotonia and brain abnormalities (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodevelopmental disorder with hypotonia and brain abnormalities; Neurodevelopmental disorder with seizures and brain abnormalities	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Neurologic; Ophthalmologic	34186028

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CLCN3 gene.

• not_provided (69 variants)
• Inborn_genetic_diseases (62 variants)
• Neurodevelopmental_disorder_with_hypotonia_and_brain_abnormalities (34 variants)
• CLCN3-related_disorder (10 variants)
• Neurodevelopmental_delay (9 variants)
• Neurodevelopmental_disorder_with_seizures_and_brain_abnormalities (4 variants)
• not_specified (2 variants)
• Neurodevelopmental_disorder (1 variants)
• CLCN3-related_neurodevelopmental_disorders (1 variants)
• Progressive_sensorineural_hearing_impairment (1 variants)
• Autism,_susceptiblity_to (1 variants)
• Complex_neurodevelopmental_disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CLCN3 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000001829.4. 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	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	7		12
missense	1	14	127	3		145
nonsense			4			4
start loss						0
frameshift	1		5			6
splice donor/acceptor (+/-2bp)			4			4
Total	2	14	145	10	0

Highest pathogenic variant AF is 0.0000020599812

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CLCN3	protein_coding	protein_coding	ENST00000347613	13	111041

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		125734	0	14	125748	0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.37	208	477	0.436	0.0000240	5660
Missense in Polyphen		90	243.58	0.36949		3026
Synonymous	1.47	147	171	0.857	0.00000928	1682
Loss of Function	5.37	4	41.2	0.0971	0.00000220	488

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000916	0.0000913
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000618	0.0000615
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000654	0.0000653
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Mediates the exchange of chloride ions against protons. Functions as antiporter and contributes to the acidification of the endosome and synaptic vesicle lumen, and may thereby affect vesicle trafficking and exocytosis. May play an important role in neuronal cell function through regulation of membrane excitability by protein kinase C. It could help neuronal cells to establish short-term memory. {ECO:0000269|PubMed:11967229}.
• Pathway: Stimuli-sensing channels;Ion channel transport;Transport of small molecules (Consensus)

Recessive Scores

• pRec: 0.245

Intolerance Scores

• loftool: 0.0597
• rvis_EVS: -0.58
• rvis_percentile_EVS: 18.59

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.945

Gene Damage Prediction

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

Gene ontology

• Biological process: regulation of pH;negative regulation of cell volume;endosomal lumen acidification;synaptic vesicle lumen acidification;chloride transmembrane transport
• Cellular component: Golgi membrane;endosome;early endosome;late endosome;Golgi apparatus;plasma membrane;integral component of plasma membrane;synaptic vesicle;external side of plasma membrane;cell surface;vesicle membrane;membrane;integral component of membrane;secretory granule;transport vesicle membrane;cytoplasmic vesicle;early endosome membrane;late endosome membrane;specific granule;phagocytic vesicle
• Molecular function: voltage-gated chloride channel activity;chloride channel activity;protein binding;ATP binding;solute:proton antiporter activity;PDZ domain binding;chloride ion binding;protein homodimerization activity;protein heterodimerization activity;volume-sensitive chloride channel activity