KCNS3

Chr 2

potassium voltage-gated channel modifier subfamily S member 3

Also known as: KV9.3

NCBI Gene: 3790 ENSG00000170745 UniProt: Q9BQ31 OMIM: 603888

KCNS3 encodes a regulatory subunit that modulates delayed rectifier potassium channels by forming heterotetrameric channels with KCNB1 and slowing down channel deactivation and inactivation kinetics. Mutations cause autosomal dominant early infantile epileptic encephalopathy with prominent developmental delay and intellectual disability. The gene shows low constraint to loss-of-function variation, suggesting tolerance to such variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Voltage-gated potassium channels form the largest and most diversified class of ion channels and are present in both excitable and nonexcitable cells. Their main functions are associated with the regulation of the resting membrane potential and the control of the shape and frequency of action potentials. The alpha subunits are of 2 types: those that are functional by themselves and those that are electrically silent but capable of modulating the activity of specific functional alpha subunits. The protein encoded by this gene is not functional by itself but can form heteromultimers with member 1 and with member 2 (and possibly other members) of the Shab-related subfamily of potassium voltage-gated channel proteins. This gene belongs to the S subfamily of the potassium channel family. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.91

Clinical Summary— KCNS3

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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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ClinVar Variants

70 VUS of 80 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.91LOEUF

pLI 0.001

Z-score 1.83

OE 0.48 (0.27–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.02Z-score

OE missense 0.83 (0.74–0.92)

234 obs / 282.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.27–0.91)

0≤0.351.4

Missense OE?0.83 (0.74–0.92)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 7 / 14.5Missense obs/exp: 234 / 282.3Syn Z: -0.70

This gene — mechanism propensity

0.79top 25%

GOF

0.88top 5%

LOF

0.2093th %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

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.

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

ClinVar Variant Classifications

80 submitted variants in ClinVar

ClinVar

Classification Summary

VUS70

Likely Benign3

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	70	0	70
Likely Benign	2	1	3
Benign	1	0	1
Total	73	1	74

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap KCNS3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →