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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene mediates sodium and chloride transport and reabsorption. The encoded protein is a membrane protein and is important in maintaining proper ionic balance and cell volume. This protein is phosphorylated in response to DNA damage. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.313 OMIM phenotypes

Clinical Summary— SLC12A2

⚡

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.

Explore recent and relevant literature in Research Assistant →

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 OE?0.19 (0.12–0.31)

0≤0.351.4

Missense OE?0.72 (0.67–0.78)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

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

This gene — mechanism propensity

0.4884th %ile

GOF

0.73top 25%

LOF

0.52top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

LOFLOEUF 0.31

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 schizophrenia1

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

References