SLC12A2

Chr 5ADAR

solute carrier family 12 member 2

Also known as: BSC, BSC-2, BSC2, CCC1, KILQS, NKCC1, PPP1R141, hNKCC1

NCBI Gene: 6558 ENSG00000064651 UniProt: P55011 OMIM: 600840

This gene encodes a cation-chloride cotransporter that mediates electroneutral transport of chloride, potassium, and sodium ions across cell membranes, playing a vital role in ionic balance and cell volume regulation. Mutations cause autosomal dominant deafness, as well as autosomal recessive Delpire-McNeill syndrome and Kilquist syndrome, which are multisystem disorders affecting neurological development and other organ systems. The gene is highly constrained against loss-of-function variants (pLI 0.96, LOEUF 0.31), indicating intolerance to protein-disrupting mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.313 OMIM phenotypes

Clinical Summary— SLC12A2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

13 unique Pathogenic / Likely Pathogenic· 100 VUS of 200 total submissions

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GeneReview available — SLC12A2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.31LOEUF

pLI 0.962

Z-score 5.77

OE 0.19 (0.12–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

2.40Z-score

OE missense 0.72 (0.67–0.78)

430 obs / 594.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.19 (0.12–0.31)

0≤0.351.4

Missense OE0.72 (0.67–0.78)

0≤0.61.4

Synonymous OE1.04

0≤1.21.6

LoF obs/exp: 11 / 58.7Missense obs/exp: 430 / 594.5Syn Z: -0.47

0.4884th %ile

GOF

0.73top 25%

LOF

0.52top 25%

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

LOF69% of P/LP variants are LoF · LOEUF 0.31

GOFprediction above median · 1 literature citation

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

GOFGain-of-function missense variant in SLC12A2, encoding the bumetanide-sensitive NKCC1 cotransporter, identified in human schizophreniaPMID:26955005

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