KCNC2

Chr 12AD

potassium voltage-gated channel subfamily C member 2

Also known as: DEE103, KV3.2

NCBI Gene: 3747ENSG00000166006UniProt: Q96PR1

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]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 103MIM #619913
AD
168
ClinVar variants
28
Pathogenic / LP
0.19
pLI score
0
Active trials
Clinical Summary— KCNC2
🧬
Gene-Disease Validity (ClinGen)
developmental and epileptic encephalopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 129 VUS of 168 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.25 (0.13–0.53)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.56 (0.50–0.63)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.20
0≤1.21.6
LoF obs/exp: 5 / 19.7Missense obs/exp: 204 / 363.7Syn Z: -2.01

ClinVar Variant Classifications

168 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic10
VUS129
Likely Benign7
Benign3
Conflicting1
18
Pathogenic
10
Likely Pathogenic
129
VUS
7
Likely Benign
3
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
8
10
0
18
Likely Pathogenic
0
9
1
0
10
VUS
6
110
13
0
129
Likely Benign
0
3
1
3
7
Benign
0
0
0
3
3
Conflicting
—1
Total6130256168

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

View in ClinVar →

Protein Context — Lollipop Plot

KCNC2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 103

MIM #619913

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — KCNC2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Novel KCNC2 variant associated with developmental and epileptic encephalopathy.
Huo L et al.·Int J Dev Neurosci
2023
A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction.
Clatot J et al.·Proc Natl Acad Sci U S A
2024Functional
Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.
Schwarz N et al.·Neurology
2022Cohort
Germline mosaicism of a missense variant in KCNC2 in a multiplex family with autism and epilepsy characterized by long-read sequencing.
Mehinovic E et al.·Am J Med Genet A
2022Case report
A recurrent de novo variant supports KCNC2 involvement in the pathogenesis of developmental and epileptic encephalopathy.
Rydzanicz M et al.·Am J Med Genet A
2021Case report
Investigation of novel de novo KCNC2 variants causing severe developmental and early-onset epileptic encephalopathy.
Li L et al.·Seizure
2022
An integrative study identifies KCNC2 as a novel predisposing factor for childhood obesity and the risk of diabetes in the Korean population.
Hwang JY et al.·Sci Rep
2016Clinical trial
Deletion of chromosome 12q21 affecting KCNC2 and ATXN7L3B in a family with neurodevelopmental delay and ataxia.
Rajakulendran S et al.·J Neurol Neurosurg Psychiatry
2013Case report
A de novo heterozygous mutation in KCNC2 gene implicated in severe developmental and epileptic encephalopathy.
Vetri L et al.·Eur J Med Genet
2020
Whole-Exome Sequencing in NF1-Related West Syndrome Leads to the Identification of KCNC2 as a Novel Candidate Gene for Epilepsy.
Rademacher A et al.·Neuropediatrics
2020Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools