KCNT1

Chr 9AD

potassium sodium-activated channel subfamily T member 1

Also known as: DEE14, EIEE14, ENFL5, KCa4.1, KNa1.1, SLACK, Slo2.2, bA100C15.2

NCBI Gene: 57582 ENSG00000107147 UniProt: Q5JUK3 OMIM: 608167

This gene encodes a sodium-activated potassium channel subunit that regulates neuronal excitability and is involved in developmental signaling pathways. Mutations cause autosomal dominant epileptic disorders including developmental and epileptic encephalopathy 14 (malignant migrating partial seizures of infancy) and nocturnal frontal lobe epilepsy. Pathogenic variants predominantly cause disease through gain-of-function effects that alter channel conductance properties.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

GOFmechanismADLOEUF 0.472 OMIM phenotypes

Clinical Summary— KCNT1

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Gene-Disease Validity (ClinGen)

childhood-onset epilepsy syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 134 VUS of 300 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KCNT1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.47LOEUF

pLI 0.000

Z-score 4.92

OE 0.32 (0.23–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

2.86Z-score

OE missense 0.72 (0.67–0.77)

571 obs / 798.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.32 (0.23–0.47)

0≤0.351.4

Missense OE0.72 (0.67–0.77)

0≤0.61.4

Synonymous OE1.25

0≤1.21.6

LoF obs/exp: 20 / 61.7Missense obs/exp: 571 / 798.3Syn Z: -3.71

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKCNT1-related epilepsyOTHERAD

definitiveKCNT1-related malignant migrating partial seizures of infancyGOFAD

0.6743th %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 · 80% of P/LP are missense

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

GOFTo date, such mutations identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), epilepsy of infancy with migrating focal seizures (EIMFS) and Ohtahara syndrome (OS) have been reported to be gain-of-function mutations (Villa and Combi, 2016).PMID:28366665

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