KCNN2

Chr 5AD

potassium calcium-activated channel subfamily N member 2

Also known as: DYT34, KCa2.2, NEDMAB, SK2, SKCA2, SKCa 2, hSK2

NCBI Gene: 3781 ENSG00000080709 UniProt: Q9H2S1 OMIM: 605879

This gene encodes a small conductance calcium-activated potassium channel that regulates neuronal excitability by mediating calcium-dependent potassium efflux and contributing to the afterhyperpolarization that follows action potentials. Mutations cause autosomal dominant dystonia 34 (myoclonic type) and neurodevelopmental disorder with variable movement or behavioral abnormalities. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.27), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.272 OMIM phenotypes

Clinical Summary— KCNN2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.27LOEUF

pLI 0.991

Z-score 4.05

OE 0.09 (0.04–0.27)

Highly constrained

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

Missense Constraint

2.29Z-score

OE missense 0.65 (0.58–0.72)

214 obs / 331.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.09 (0.04–0.27)

0≤0.351.4

Missense OE0.65 (0.58–0.72)

0≤0.61.4

Synonymous OE1.26

0≤1.21.6

LoF obs/exp: 2 / 22.9Missense obs/exp: 214 / 331.0Syn Z: -2.31

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateKCNN2-related neurodevelopmental disorder with or without movement disorderLOFAD

0.6549th %ile

GOF

0.76top 25%

LOF

0.64top 25%

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

LOF1 literature citation · LOEUF 0.27

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.

Literature Evidence

LOFAltogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.PMID:33242881

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