SLC12A5

Chr 20ADAR

solute carrier family 12 member 5

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

NCBI Gene: 57468 ENSG00000124140 UniProt: Q9H2X9 OMIM: 606726

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 OMIM 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 OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Epilepsy, idiopathic generalized, susceptibility to, 14}MIM #616685

Developmental and epileptic encephalopathy 34MIM #616645

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Strong · developmental and epileptic encephalopathy, 34 · AR · Labcorp Genetics (formerly Invitae)
Strong · epilepsy of infancy with migrating focal seizures · AR · G2P
Limited · genetic developmental and epileptic encephalopathy · AR · ClinGen 2023 — not for standalone diagnostic reporting
Limited · epilepsy, idiopathic generalized, susceptibility to, 14 · AD · Ambry Genetics — not for standalone diagnostic reporting

+1 more curated pair

Interpreting a novel variant

Loss of function is the established mechanism and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.14

LOEUF· LoF intol.

LOF

Mechanism· annotated

📖

GeneReview available — SLC12A5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in SLC12A5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 51

1,179 rare PASS variants

Rare truncating (LoF)

1 in 500

108 rare PASS variants

Rare synonymous (reference)

1 in 55

732 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SLC12A5. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 57	1 in 850
South Asian	~43k	1 in 58	1 in 270
Remaining (unassigned)	~30k	1 in 53	1 in 320
European (Finnish)	~27k	1 in 150	1 in 970
Admixed American	~22k	1 in 43	1 in 260
African / African American	~21k	1 in 42	1 in 160
East Asian	~20k	1 in 76	1 in 710
Ashkenazi Jewish	~13k	1 in 140	1 in 2,400
Middle Eastern	~2,884	1 in 52	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 26 coding exons well covered in gnomAD exomes and genomes.? see exons ↓