CLCN2

protein-coding

chloride voltage-gated channel 2, the group of Chloride voltage-gated channels

Gene summary

This gene encodes a voltage-gated chloride channel. The encoded protein is a transmembrane protein that maintains chloride ion homeostasis in various cells. Defects in this gene may be a cause of certain epilepsies. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

MANE transcript

NM_004366.6

Inheritance

AR, AD

ClinVar variants

P:47U:410B:146

Top phenotype

Hyperaldosteronism, familial, type II

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr3:184,346,185-184,361,650

External References & Databases

Ensembl (ENSG00000114859)

Transcript & Mutation Effects

hg38 • Region Span ~15.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

leukoencephalopathy with mild cerebellar ataxia and white matter edemaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014292

Submitter: Ambry Genetics

familial hyperaldosteronism type IIMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011576

Submitter: Ambry Genetics

epilepsy, idiopathic generalized, susceptibility to, 11STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011875

Submitter: Genomics England PanelApp

leukoencephalopathy with mild cerebellar ataxia and white matter edemaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014292

Submitter: Labcorp Genetics (formerly Invitae)

epilepsyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: ClinGen

*CLCN2* was first reported in association with disease in 2003 when Haug and colleagues identified *CLCN2* variants in patients with idiopathic generalized epilepsies (PMID:12612585). Over time, variants in this gene have been associated with various presentations: autosomal recessive leukoencephalopathy with ataxia,autosomal dominant familial hyperaldosteronism, and multiple autosomal dominant epilepsy presentations including idiopathic generalized epilepsy (IGE), juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy (JME). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in phenotypic variability or disease mechanism among the autosomal dominant epilepsy disease assertions. Therefore, this curation will be performed using the term “epilepsy,” which includes cases exhibiting the following disease entities: IGE, JAE, and JME. The gene-disease relationship between *CLCN2* and autosomal recessive leukoencephalopathy with ataxia and familial hyperaldosteronism may be assessed separately. Haug et al. identified three variants in the *CLCN2* gene in three of forty-six unrelated families with IGE localized to 3q26, which included several of the families reported in an original linkage study by Sander et al. (PMID:10888596). Later in 2009, Kleefuβ-Lie et al. (PMID:19710712) re-evaluated two of the families reported by Haug et al.and identified inconsistencies in the family structure, phenotype, and genetic analysis. This led to the retraction of the Haug et al. paper (PMID:19710717). Blanz et al. (2007, PMID:17567819) presented two variants in *CLCN2* previously reported in individuals with epilepsy; however, the probands in Blanz et al. with these variants had leukodystrophy without epilepsy. These authors postulated that these variants were therefore not related to epilepsy or leukodystrophy. Later, Saint-Martin et al. (2009, PMID:19191339) identified heterozygous variants in *CLCN2* in families with JME and IGE, but these variants were present in unaffected fathers. These authors concluded that either variants in *CLCN2* cause epilepsy with reduced penetrance, or additional unidentified factors are necessary for full phenotypic expression. Therefore, none of these variants were scored as a part of this curation. In a mouse model published by Blanz et al. (2007, PMID:17567819), authors found that neither the heterozygous nor the homozygous *CLCN2* knockout mice demonstrated lowered seizure thresholds. Therefore, the model was not scored in this curation. In summary, the evidence supporting the relationship between *CLCN2* and autosomal dominant epilepsy has been refuted and no valid evidence remains to support the claim. This classification was approved by the ClinGen Epilepsy Expert Panel on the meeting date March 15, 2022 (SOP Version 8).

leukoencephalopathy with mild cerebellar ataxia and white matter edemaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014292

Submitter: Orphanet

familial hyperaldosteronism type IISUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011576

Submitter: Orphanet

leukoencephalopathy with mild cerebellar ataxia and white matter edemaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014292

Submitter: Genomics England PanelApp

leukoencephalopathy with mild cerebellar ataxia and white matter edemaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014292

Submitter: G2P

Clinical Genomic Database (CGD)

Hyperaldosteronism, familial, type IIAD

Manifestation: Endocrine; Neurologic

Intervention: Endocrine

Rationale: The condition may manifest with features of hyperadolsteronism including hypertension and hypokalemia, and awareness may allow prompt medical management (eg, with spironolactone)

Comments: Functional proof of pathogenicity in reported epilepsy-related dominant conditions is controversial; As with other forms of epilepsy, optimal seizure control is advantageous

Refs: 10888596; 12612585; 19710712; 19191339; 20037607; 23707145; 29403011; 29403012

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLCN2 variants in ClinVar

20 Conditions Cataloged

not providedTotal: 490

Leukoencephalopathy with mild cerebellar ataxia and white matter edemaTotal: 199

Familial hyperaldosteronism type IITotal: 180

Epilepsy, idiopathic generalized, susceptibility to, 11Total: 178

Inborn genetic diseasesTotal: 153

not specifiedTotal: 106

CLCN2-related disorderTotal: 39

Intellectual disabilityTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004366.6. 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			15 clinvar	112 clinvar		127
missense	5 clinvar	4 clinvar	377 clinvar	34 clinvar		420
nonsense	4 clinvar	7 clinvar	4 clinvar			15
start loss			1 clinvar			1
frameshift	10 clinvar	7 clinvar	4 clinvar			21
splice donor/acceptor (+/-2bp)	1 clinvar	9 clinvar	9 clinvar			19
Total	20	27	410	146	0	603

Highest pathogenic variant AF is 0.000078070494

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004366.6	RefSeq	NP_004357.3	24	MANE Select
ENST00000265593.9	Ensembl	ENSP00000265593.4	24	MANE Select
NM_001171087.3	RefSeq	NP_001164558.1	24	Standard
NM_001171088.3	RefSeq	NP_001164559.1	23	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
clcn2c	Danio rerio	Structure: chloride transport Quality: process quality abnormal

Gene / Model

Organism

Observed Phenotype

clcn2c

Danio rerio

Structure: chloride transport

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Mineral absorption - Homo sapiens (human)
Stimuli-sensing channels
Ion channel transport
Transport of small molecules

Biological Process

regulation of aldosterone biosynthetic process
ion transmembrane transport
regulation of ion transmembrane transport
retina development in camera-type eye
cell differentiation involved in salivary gland development

Molecular Function

voltage-gated chloride channel activity

Cellular Component

plasma membrane
integral component of plasma membrane
chloride channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265593
Coding exons: 24
Length: 15467
Individuals with no LoFs: 125653
Homozygous LoFs: 0
Heterozygous LoFs: 95
Defined: 125748
p: 0.000378

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.654	494	537	0.921	0.0000364	5763
Missense (PolyPhen)		179	215.59	0.83029		2322
Synonymous	-0.971	229	211	1.08	0.0000134	1906
Loss of Function	2.83	26	46.9	0.554	0.00000265	513

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00093	0.00092	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000046	rare
European (Non-Finnish)	0.00051	0.00050	rare
South Asian	0.00033	0.00033	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume; membrane potential stabilization, signal transduction and transepithelial transport. {ECO:0000269|PubMed:19153159, ECO:0000269|PubMed:19191339}.;
Disease: DISEASE: Epilepsy, idiopathic generalized 11 (EIG11) [MIM:607628]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. {ECO:0000269|PubMed:19191339}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Juvenile absence epilepsy 2 (JAE2) [MIM:607628]: A subtype of idiopathic generalized epilepsy characterized by onset occurring around puberty, absence seizures, generalized tonic- clonic seizures (GTCS), GTCS on awakening, and myoclonic seizures. {ECO:0000269|PubMed:19710712}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.; DISEASE: Juvenile myoclonic epilepsy 8 (EJM8) [MIM:607628]: A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue. {ECO:0000269|PubMed:19191339}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Leukoencephalopathy with ataxia (LKPAT) [MIM:615651]: An autosomal recessive neurologic disorder with a characteristic pattern of white matter abnormalities on brain MRI. Affected individuals have prominent signal abnormalities and decreased apparent diffusion coefficient values in the posterior limbs of the internal capsules, middle cerebral peduncles, pyramidal tracts in the pons, and middle cerebellar peduncles, suggesting myelin microvacuolation. Clinical features include ataxia and unstable gait. More variable abnormalities may include visual field defects, headaches, and learning disabilities. {ECO:0000269|PubMed:23707145}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.187

Intolerance Scores

LoFtool: 0.0114
RVIS EVS: 0.5
RVIS percentile EVS: 79.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.220

Gene Damage Prediction

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