KCNC2

Chr 12AD

potassium voltage-gated channel subfamily C member 2

Also known as: DEE103, KV3.2

NCBI Gene: 3747 ENSG00000166006 UniProt: Q96PR1 OMIM: 176256

The protein forms voltage-gated potassium channels that mediate fast action potential repolarization and enable sustained high-frequency firing in central nervous system neurons, particularly in GABAergic interneurons and cells involved in gamma oscillations. Mutations cause developmental and epileptic encephalopathy 103 through an autosomal dominant inheritance pattern via a gain-of-function mechanism. The altered channel function disrupts neuronal excitability and synaptic transmission, leading to seizures and developmental impairment.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and is comprised of four subfamilies. Based on sequence similarity, this gene is similar to one of these subfamilies, namely the Shaw subfamily. The protein encoded by this gene belongs to the delayed rectifier class of channel proteins and is an integral membrane protein that mediates the voltage-dependent potassium ion permeability of excitable membranes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.531 OMIM phenotype

Clinical Summary— KCNC2

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · 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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ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 123 VUS of 158 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KCNC2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.189

Z-score 3.07

OE 0.25 (0.13–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.98Z-score

OE missense 0.56 (0.50–0.63)

204 obs / 363.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.25 (0.13–0.53)

0≤0.351.4

Missense OE?0.56 (0.50–0.63)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 5 / 19.7Missense obs/exp: 204 / 363.7Syn Z: -2.01

This gene — mechanism propensity

0.79top 25%

GOF

0.85top 5%

LOF

0.3454th %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 · 100% 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

GOFFunctional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms.DISCUSSION: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical1

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

References

1.PMID 35314505 ↗

ClinVar Variant Classifications

158 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic9

VUS123

Likely Benign12

Benign3

Conflicting1

Pathogenic

Likely Pathogenic

123

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	8	0	0	8
Likely Pathogenic	0	9	0	0	9
VUS	7	115	1	0	123
Likely Benign	0	4	1	7	12
Benign	0	0	0	3	3
Conflicting	—				1
Total	7	136	2	10	156

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap KCNC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →