SLC12A7

Chr 5

solute carrier family 12 member 7

ENSG00000113504 UniProt: Q9Y666 OMIM: 604879

The SLC12A7 protein mediates electroneutral potassium-chloride cotransport and is important for potassium recycling in the inner ear and chloride handling in the kidney. Mutations cause autosomal recessive sensorineural hearing loss with or without renal tubular acidosis. This gene is extremely intolerant to loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

Mediates electroneutral potassium-chloride cotransport when activated by cell swelling (PubMed:10913127). May mediate K(+) uptake into Deiters' cells in the cochlea and contribute to K(+) recycling in the inner ear. Important for the survival of cochlear outer and inner hair cells and the maintenance of the organ of Corti. May be required for basolateral Cl(-) extrusion in the kidney and contribute to renal acidification (By similarity)

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.89

Clinical Summary— SLC12A7

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Gene-Disease Validity (ClinGen)

renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss · UDNo Known Disease Relationship

No known disease relationship

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.89LOEUF

pLI 0.000

Z-score 2.23

OE 0.67 (0.51–0.89)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.32Z-score

OE missense 0.86 (0.81–0.92)

622 obs / 722.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.67 (0.51–0.89)

0≤0.351.4

Missense OE?0.86 (0.81–0.92)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 35 / 52.4Missense obs/exp: 622 / 722.0Syn Z: -3.05

This gene — mechanism propensity

0.7325th %ile

GOF

0.82top 10%

LOF

0.2289th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). 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

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.