CLCN6

Chr 1

Cl-/H+ antiporter 6

Also known as: CLC-6, CONRIBA

NCBI Gene: 1185 ENSG00000011021 UniProt: P51797

The protein functions as a voltage-gated chloride/proton antiporter that contributes to acidification of late endosome lumens. Mutations cause Neuronal ceroid lipofuscinosis 7, an autosomal recessive lysosomal storage disorder characterized by progressive neurodegeneration with seizures, vision loss, and cognitive decline typically beginning in late infancy to early childhood. The gene shows moderate constraint against loss-of-function variants, indicating intolerance to complete protein loss.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the voltage-dependent chloride channel protein family. Members of this family can function as either chloride channels or antiporters. This protein is primarily localized to late endosomes and functions as a chloride/proton antiporter. Alternate splicing results in both coding and non-coding variants. Additional alternately spliced variants have been described but their full-length structure is unknown. [provided by RefSeq, Mar 2012]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.61

Clinical Summary— CLCN6

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Gene-Disease Validity (ClinGen)

neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities · ADModerate

Moderate evidence — consider for supplementary testing

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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

2 unique Pathogenic / Likely Pathogenic· 549 VUS of 1058 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.000

Z-score 3.78

OE 0.42 (0.30–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.59Z-score

OE missense 0.81 (0.75–0.87)

439 obs / 543.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.42 (0.30–0.61)

0≤0.351.4

Missense OE?0.81 (0.75–0.87)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 21 / 49.7Missense obs/exp: 439 / 543.5Syn Z: -0.89

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCLCN6-related developmental disorderOTHERAD

This gene — mechanism propensity

0.76top 25%

GOF

0.75top 25%

LOF

0.2385th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFA Recurrent Gain-of-Function Mutation in CLCN6, Encoding the ClC-6 Cl -/H +-Exchanger, Causes Early-Onset Neurodegeneration1

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

References

1.PMID 33217309 ↗

ClinVar Variant Classifications

1058 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS549

Likely Benign433

Benign39

Conflicting4

Pathogenic

549

VUS

433

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	0	0	0	0	0
VUS	33	473	32	11	549
Likely Benign	0	8	211	214	433
Benign	0	1	23	15	39
Conflicting	—				4
Total	33	484	266	240	1,027

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 58) ClinVar copy-number / structural variants overlap CLCN6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →