SLC12A5

Chr 20

solute carrier family 12 member 5

Also known as: DEE34, EIEE34, EIG14, KCC2, hKCC2

NCBI Gene: 57468 ENSG00000124140 UniProt: Q9H2X9

The encoded protein is a neuronal potassium-chloride cotransporter that maintains low intracellular chloride levels required for proper GABA-mediated inhibition and is involved in dendritic spine formation and maturation. Mutations cause developmental and epileptic encephalopathy 34 and idiopathic generalized epilepsy through both autosomal dominant and autosomal recessive inheritance patterns. The gene is highly intolerant to loss-of-function variants, and disease predominantly results from haploinsufficiency, though the dual inheritance patterns suggest variant-dependent mechanisms of pathogenicity.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

K-Cl cotransporters are proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The protein encoded by this gene is an integral membrane K-Cl cotransporter that can function in either a net efflux or influx pathway, depending on the chemical concentration gradients of potassium and chloride. The encoded protein can act as a homomultimer, or as a heteromultimer with other K-Cl cotransporters, to maintain chloride homeostasis in neurons. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Sep 2008]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.14

Clinical Summary— SLC12A5

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ARLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

36 unique Pathogenic / Likely Pathogenic· 281 VUS of 739 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SLC12A5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.14LOEUF

pLI 1.000

Z-score 6.58

OE 0.05 (0.02–0.14)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.70Z-score

OE missense 0.50 (0.46–0.55)

347 obs / 696.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.14)

0≤0.351.4

Missense OE?0.50 (0.46–0.55)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 3 / 56.3Missense obs/exp: 347 / 696.1Syn Z: 1.01

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSLC12A5-related epilepsy of infancy with migrating focal seizuresOTHERAR

Mechanism Note (expert annotation)

LOF

KCC2 potassium-chloride cotransporter. LOF variants reduce chloride extrusion capacity, impairing GABAergic inhibition and causing DEE. GOF is not an established mechanism.1

This gene — mechanism propensity

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

0.5180th %ile

GOF

0.75top 25%

LOF

0.48top 25%

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.

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 26028587 ↗

ClinVar Variant Classifications

739 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25

Likely Pathogenic11

VUS281

Likely Benign356

Benign39

Conflicting18

Pathogenic

Likely Pathogenic

281

VUS

356

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	22	1	2	0	25
Likely Pathogenic	7	4	0	0	11
VUS	2	258	17	4	281
Likely Benign	0	3	127	226	356
Benign	0	1	26	12	39
Conflicting	—				18
Total	31	267	172	242	730

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap SLC12A5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →