SLC12A6

Chr 15ARAD

solute carrier family 12 member 6

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

NCBI Gene: 9990 ENSG00000140199 UniProt: Q9UHW9 OMIM: 604878

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the K-Cl cotransporter (KCC) family. K-Cl cotransporters are integral membrane proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The proteins encoded by this gene are activated by cell swelling induced by hypotonic conditions. Alternate splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are associated with agenesis of the corpus callosum with peripheral neuropathy. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.402 OMIM phenotypes

Clinical Summary— SLC12A6

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

242 unique Pathogenic / Likely Pathogenic· 599 VUS of 1804 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SLC12A6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.40LOEUF

pLI 0.011

Z-score 5.49

OE 0.26 (0.18–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.96Z-score

OE missense 0.67 (0.62–0.73)

436 obs / 648.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.26 (0.18–0.40)

0≤0.351.4

Missense OE?0.67 (0.62–0.73)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

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

This gene — mechanism propensity

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

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.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 33323309 ↗

ClinVar Variant Classifications

1804 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic68

Likely Pathogenic174

VUS599

Likely Benign821

Benign96

Conflicting32

Pathogenic

174

Likely Pathogenic

599

VUS

821

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	59	4	5	0	68
Likely Pathogenic	167	5	2	0	174
VUS	8	469	94	28	599
Likely Benign	4	5	363	449	821
Benign	0	1	86	9	96
Conflicting	—				32
Total	238	484	550	486	1,790

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap SLC12A6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →