CLCN2

Chr 3ADAR

chloride voltage-gated channel 2

Also known as: CIC-2, CLC2, ECA2, ECA3, EGI11, EGI3, EGMA, EJM6

NCBI Gene: 1181 ENSG00000114859 UniProt: P51788 OMIM: 600570

This gene encodes a voltage-gated chloride channel that maintains chloride ion homeostasis and regulates neuronal excitability, aldosterone production in adrenal glands, and chloride flux in glial cells. Mutations cause leukoencephalopathy with ataxia, familial hyperaldosteronism type II, and susceptibility to various epilepsy syndromes including juvenile absence epilepsy and juvenile myoclonic epilepsy. Inheritance follows both autosomal dominant and autosomal recessive patterns depending on the specific condition.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.775 OMIM phenotypes

Clinical Summary— CLCN2

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Gene-Disease Validity (ClinGen)

epilepsy · ADRefuted

Refuted — evidence has disproved this relationship

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

46 unique Pathogenic / Likely Pathogenic· 370 VUS of 706 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CLCN2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.77LOEUF

pLI 0.000

Z-score 2.83

OE 0.55 (0.41–0.77)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.65Z-score

OE missense 0.92 (0.85–0.99)

494 obs / 536.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.55 (0.41–0.77)

0≤0.351.4

Missense OE?0.92 (0.85–0.99)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 26 / 46.9Missense obs/exp: 494 / 536.6Syn Z: -0.97

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCLCN2-related leukoencephalopathy with ataxiaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.80top 10%

GOF

0.78top 25%

LOF

0.2386th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

GOFA gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 29403012 ↗

ClinVar Variant Classifications

706 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22

Likely Pathogenic24

VUS370

Likely Benign204

Benign23

Conflicting29

Pathogenic

Likely Pathogenic

370

VUS

204

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	16	6	0	0	22
Likely Pathogenic	21	3	0	0	24
VUS	5	334	19	12	370
Likely Benign	0	16	88	100	204
Benign	0	4	15	4	23
Conflicting	—				29
Total	42	363	122	116	672

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

42 pathogenic / likely-pathogenic (of 48) ClinVar copy-number / structural variants overlap CLCN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →