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

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]

Primary Disease Associations & Inheritance

{Epilepsy, idiopathic generalized, susceptibility to, 11}MIM #607628

{Epilepsy, juvenile absence, susceptibility to, 2}MIM #607628

{Epilepsy, juvenile myoclonic, susceptibility to, 8}MIM #607628

Hyperaldosteronism, familial, type IIMIM #605635

Leukoencephalopathy with ataxiaMIM #615651

UniProtJuvenile absence epilepsy 2

746

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— CLCN2

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

20 Pathogenic / Likely Pathogenic· 131 VUS of 746 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.77LOEUF

pLI 0.000

Z-score 2.83

OE 0.55 (0.41–0.77)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.65Z-score

OE missense 0.92 (0.85–0.99)

494 obs / 536.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.55 (0.41–0.77)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.85–0.99)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.09

0≤1.21.6

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

ClinVar Variant Classifications

746 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic8

VUS131

Likely Benign45

Benign2

Conflicting2

Pathogenic

Likely Pathogenic

131

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	0	8	0	12
Likely Pathogenic	5	0	3	0	8
VUS	2	112	11	6	131
Likely Benign	0	2	23	20	45
Benign	0	0	2	0	2
Conflicting	—				2
Total	11	114	47	26	200

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

View in ClinVar →

Protein Context — Lollipop Plot

CLCN2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CLCN2-related leukoencephalopathy with ataxia

definitive

ARLoss Of FunctionAbsent Gene Product

Eye

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

CHLORIDE CHANNEL 2; CLCN2

MIM #600570 · *

{Epilepsy, idiopathic generalized, susceptibility to, 11}

MIM #607628