CLCN3

protein-coding

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

Gene summary

This gene encodes a member of the voltage-gated chloride channel (ClC) family. The encoded protein is present in all cell types and localized in plasma membranes and in intracellular vesicles. It is a multi-pass membrane protein which contains a ClC domain and two additional C-terminal CBS (cystathionine beta-synthase) domains. The ClC domain catalyzes the selective flow of Cl- ions across cell membranes, and the CBS domain may have a regulatory function. This protein plays a role in both acidification and transmitter loading of GABAergic synaptic vesicles, and in smooth muscle cell activation and neointima formation. This protein is required for lysophosphatidic acid (LPA)-activated Cl- current activity and fibroblast-to-myofibroblast differentiation. The protein activity is regulated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in glioma cells. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

MANE transcript

NM_001829.4

Inheritance

AD, AR

ClinVar variants

P:16U:179B:21

Top phenotype

Neurodevelopmental disorder with hypotonia and brain abnormalities; Neurodevelopmental disorder with seizures and brain abnormalities

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr4:169,612,633-169,723,673

External References & Databases

Ensembl (ENSG00000109572)

Transcript & Mutation Effects

hg38 • Region Span ~111.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Illumina

neurodevelopmental disorder with hypotonia and brain abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859187

Submitter: G2P

neurodevelopmental disorder with hypotonia and brain abnormalitiesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859187

Submitter: Broad Center for Mendelian Genomics

neurodevelopmental disorder with hypotonia and brain abnormalitiesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859187

Submitter: Ambry Genetics

neurodevelopmental disorder with seizures and brain abnormalitiesLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859188

Submitter: Ambry Genetics

neurodevelopmental disorder with seizures and brain abnormalitiesLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859188

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with hypotonia and brain abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859187

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with seizures and brain abnormalitiesLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859188

Submitter: G2P

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with hypotonia and brain abnormalities; Neurodevelopmental disorder with seizures and brain abnormalitiesAD/AR

Manifestation: Craniofacial; Neurologic; Ophthalmologic

Intervention: General

Rationale: 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

Refs: 34186028

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLCN3 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 89

Inborn genetic diseasesTotal: 72

Neurodevelopmental disorder with hypotonia and brain abnormalitiesTotal: 40

CLCN3-related disorderTotal: 14

not specifiedTotal: 10

Neurodevelopmental delayTotal: 9

Neurodevelopmental disorder with seizures and brain abnormalitiesTotal: 9

Complex neurodevelopmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001829.4. 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			5 clinvar	17 clinvar		22
missense	2 clinvar	13 clinvar	159 clinvar	4 clinvar		178
nonsense			4 clinvar			4
start loss						0
frameshift	1 clinvar		6 clinvar			7
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	3	13	179	21	0	216

Highest pathogenic variant AF is 0.0000020599812

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001829.4	RefSeq	NP_001820.2	12	MANE Select
ENST00000513761.6	Ensembl	ENSP00000424603.1	12	MANE Select
NM_001243372.2	RefSeq	NP_001230301.1	11	Standard
NM_001243374.2	RefSeq	NP_001230303.2	12	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

regulation of pH
negative regulation of cell volume
endosomal lumen acidification
synaptic vesicle lumen acidification
chloride transmembrane transport

Molecular Function

voltage-gated chloride channel activity
chloride channel activity
protein binding
ATP binding
solute:proton antiporter activity

Cellular Component

Golgi membrane
endosome
early endosome
late endosome
Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000347613
Coding exons: 13
Length: 111041
Individuals with no LoFs: 125734
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125748
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.37	208	477	0.436	0.0000240	5660
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.245

Intolerance Scores

LoFtool: 0.0597
RVIS EVS: -0.58
RVIS percentile EVS: 18.59

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.945

Gene Damage Prediction

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