KCNT2

Chr 1

potassium sodium-activated channel subfamily T member 2

Also known as: DEE57, EIEE57, KCa4.2, KNa1.2, SLICK, SLO2.1

NCBI Gene: 343450 ENSG00000162687 UniProt: Q6UVM3

The protein functions as a sodium-activated and chloride-activated potassium channel that regulates neuronal excitability by producing outward rectifier K+ currents across the plasma membrane. Mutations cause developmental and epileptic encephalopathy 57, characterized by early-onset seizures and developmental delays. The condition follows autosomal dominant inheritance, and the gene is highly constrained against loss-of-function variants (LOEUF 0.374).

ResearchSummary from RefSeq, OMIM, UniProt

Enables chloride-activated potassium channel activity and intracellular sodium-activated potassium channel activity. Involved in potassium ion export across plasma membrane. Located in plasma membrane. Implicated in developmental and epileptic encephalopathy 57. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.37

Clinical Summary— KCNT2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.37LOEUF

pLI 0.042

Z-score 5.74

OE 0.25 (0.17–0.37)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.56Z-score

OE missense 0.58 (0.53–0.64)

340 obs / 581.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.25 (0.17–0.37)

0≤0.351.4

Missense OE?0.58 (0.53–0.64)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 17 / 68.1Missense obs/exp: 340 / 581.7Syn Z: -1.10

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedKCNT2-related developmental and infantile epileptic encephalopathyGOFAD

This gene — mechanism propensity

0.6260th %ile

GOF

0.73top 25%

LOF

0.3065th %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 · 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

GOFDe novo gain-of-function variants in KCNT2 as a novel cause of developmental and epileptic encephalopathy.1

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

References