SLC12A6

Chr 15ARAD

solute carrier family 12 member 6

Also known as: ACCPN, CMT2II, KCC3, KCC3A, KCC3B

This gene encodes a potassium-chloride cotransporter that maintains cellular chloride concentrations and contributes to cell volume regulation by mediating electroneutral ion transport when cells swell. Mutations cause agenesis of the corpus callosum with peripheral neuropathy and Charcot-Marie-Tooth disease type 2II, inherited in both autosomal recessive and autosomal dominant patterns. The gene is highly intolerant to loss-of-function variants (LOEUF 0.395), indicating that complete protein loss is likely deleterious.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismAR/ADLOEUF 0.402 OMIM phenotypes
Clinical SummarySLC12A6
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Moderate LoF intolerance
LoF Constraint
0.40LOEUF
pLI 0.011
Z-score 5.49
OE 0.26 (0.180.40)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.96Z-score
OE missense 0.67 (0.620.73)
436 obs / 648.0 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.26 (0.180.40)
00.351.4
Missense OE0.67 (0.620.73)
00.61.4
Synonymous OE0.99
01.21.6
LoF obs/exp: 17 / 64.6Missense obs/exp: 436 / 648.0Syn Z: 0.08
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveSLC12A6-related agenesis of the corpus callosum with peripheral neuropathyLOFAR

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

DN
0.7327th %ile
GOF
0.82top 10%
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

DNOur findings expand the genotypic and phenotypic spectrum associated with SLC12A6 mutations from AR-HMSN/ACC to AD-CMT. The differences in the inheritance pattern might be associated with a dominant-negative pathomechanism.PMID:33323309

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

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

SLC12A6 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗