SLC30A8

Chr 8AD

solute carrier family 30 member 8

Also known as: ZNT8, ZnT-8

NCBI Gene: 169026 ENSG00000164756 UniProt: Q8IWU4 OMIM: 611145

The protein functions as a proton-coupled zinc antiporter that transports zinc into pancreatic beta cell secretory granules to regulate insulin secretion. Mutations cause autosomal dominant susceptibility to type 2 diabetes mellitus (noninsulin-dependent diabetes). The gene shows extremely low constraint against loss-of-function variants (pLI near zero), suggesting tolerance to such changes.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a zinc efflux transporter involved in the accumulation of zinc in intracellular vesicles. This gene is expressed at a high level only in the pancreas, particularly in islets of Langerhans. The encoded protein colocalizes with insulin in the secretory pathway granules of the insulin-secreting INS-1 cells. Allelic variants of this gene exist that confer susceptibility to diabetes mellitus, noninsulin-dependent (NIDDM). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.511 OMIM phenotype

Clinical Summary— SLC30A8

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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?

1.51LOEUF

pLI 0.000

Z-score -0.05

OE 1.01 (0.69–1.51)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.11Z-score

OE missense 0.98 (0.87–1.10)

200 obs / 204.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.01 (0.69–1.51)

0≤0.351.4

Missense OE?0.98 (0.87–1.10)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 17 / 16.8Missense obs/exp: 200 / 204.4Syn Z: 0.91

This gene — mechanism propensity

0.81top 10%

GOF

0.73top 25%

LOF

0.2583th %ile

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

GOFprediction above median · 1 literature citation

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.

Literature Evidence

GOFHere, we clarify this incongruence, showing that rs13266634 boosts the activity of an overlapping enhancer and suggesting an SLC30A8 gain of function as the cause for the increased risk for the disease.1

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

References