SLC12A2

Chr 5ADAR

solute carrier family 12 member 2

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

NCBI Gene: 6558ENSG00000064651UniProt: P55011

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]

Primary Disease Associations & Inheritance

Deafness, autosomal dominant 78MIM #619081
AD
Delpire-McNeill syndromeMIM #619083
AD
Kilquist syndromeMIM #619080
AR
578
ClinVar variants
45
Pathogenic / LP
0.96
pLI score· haploinsufficient
0
Active trials
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.
📋
ClinVar Variants
45 Pathogenic / Likely Pathogenic· 315 VUS of 578 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.19 (0.12–0.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.67–0.78)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.04
0≤1.21.6
LoF obs/exp: 11 / 58.7Missense obs/exp: 430 / 594.5Syn Z: -0.47

ClinVar Variant Classifications

578 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic15
VUS315
Likely Benign169
Benign34
Conflicting15
30
Pathogenic
15
Likely Pathogenic
315
VUS
169
Likely Benign
34
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
5
21
0
30
Likely Pathogenic
7
0
8
0
15
VUS
11
272
30
2
315
Likely Benign
0
10
77
82
169
Benign
0
2
28
4
34
Conflicting
—15
Total2228916488578

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC12A2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Deafness, autosomal dominant 78

MIM #619081

Molecular basis of disorder known

Autosomal dominant

Delpire-McNeill syndrome

MIM #619083

Molecular basis of disorder known

Autosomal dominant

Kilquist syndrome

MIM #619080

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — SLC12A2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Expanding the genetic heterogeneity of intellectual disability.
Anazi S et al.·Hum Genet
2017
Exosome-derived SLC12A2-DT promotes macrophage M2 polarization-mediated hepatocellular carcinoma progression.
Zhou J et al.·Int Immunopharmacol
2025
Bartter syndrome.
Hebert SC·Curr Opin Nephrol Hypertens
2003Review
Clinical characterization and further confirmation of the autosomal recessive SLC12A2 disease.
Bilal Shamsi M et al.·J Hum Genet
2021
NKCC1 in human diseases: is the SLC12A2 gene haploinsufficient?
Delpire E et al.·Am J Physiol Cell Physiol
2023
PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic heterogeneity among hearing impaired assortative mating families in Southern India.
Vanniya S P et al.·Ann Hum Genet
2022
Identification and Characterization of a Novel Biallelic SLC12A2 Variant Associated With Kilquist Syndrome (OMIM #619080).
Leone P et al.·Am J Med Genet A
2025Case report
Physiology and pathophysiology of SLC12A1/2 transporters.
Markadieu N et al.·Pflugers Arch
2014Review
Further confirmation of the association of SLC12A2 with non-syndromic autosomal-dominant hearing impairment.
Adadey SM et al.·J Hum Genet
2021
NKCC1: Newly Found as a Human Disease-Causing Ion Transporter.
Koumangoye R et al.·Function (Oxf)
2021Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools