KCNC1
protein-codingpotassium voltage-gated channel subfamily C member 1, the group of Potassium voltage-gated channels
Gene summary
This gene encodes a member of a family of integral membrane proteins that mediate the voltage-dependent potassium ion permeability of excitable membranes. Alternative splicing is thought to result in two transcript variants encoding isoforms that differ at their C-termini. These isoforms have had conflicting names in the literature: the longer isoform has been called both "b" and "alpha", while the shorter isoform has been called both "a" and "beta" (PMIDs 1432046, 12091563). [provided by RefSeq, Oct 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~122.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014521
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014521
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014521
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014521
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0020074
Submitter: ClinGen
KCNC1 was first reported in relation to autosomal dominant progressive myoclonus epilepsy (PME) in thirteen unrelated families with the same recurrent variant, c.959G>A (p.Arg320His), in 2015 (Muona et al. 2015, PMID: 25401298). Since then, eight more families with PME and the same variant have been reported in six studies. Patients with this condition initially develop normally, but have generalized tonic-clonic seizures, myoclonus seizures, myoclonus, cognitive and motor decline, and ataxia. The onset varies from 3 to 14 years of age. In addition to PME, KCNC1 is also associated with autosomal dominant complex neurodevelopmental disorder, which is curated separately. The mechanism of pathogenicity of the p.Arg320His variant appears to be dominant negative according to functional studies. The variant was confirmed de novo in 12 probands who received 1 pt each. The other 9 families received 0.5 pts each. One family with a different variant, c.949C>A, p.Arg317Ser, also had PME, and received 0.5 pts, because a functional study of the variant revealed a dominant negative effect. In total, maximum score for genetic evidence (12 pts) has been reached. In summary, KCNC1 is definitively associated with autosomal dominant progressive myoclonus epilepsy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
KCNC1 was first reported in relation to autosomal dominant complex neurodevelopmental disorder (CND) in a family in 2017 (Poirier et al. 2017 PMID: 28145425). Since then, seven variants in 15 families with CND have been reported in four studies. The phenotypes of patients with KCNC1-related CND vary from developmental delay/intellectual disability and hypotonia without seizures to seizures, global developmental delay, hypotonia, and ataxia. The onset varies from birth to 3 years of age. There is a recurrent variant, p.Ala421Val, which is associated with severe phenotypes with myoclonic and generalized tonic clonic seizures and intellectual disability. In addition to CND, KCNC1 is also associated with autosomal dominant progressive myoclonus epilepsy, which is curated separately. The mechanism of pathogenicity appears to be loss of function and dominant negative. Of the 15 reported probands, two had loss-of-function variants inherited from a parent and each received 1.5 pts. Of the remaining 13 families, 12 had de novo variants and received 0.5pt. Of these 12 families de novo variants, 11 had variants with their effects verified by functional studies and received additional 0.5 pts each. In total, maximum score for genetic evidence (12 pts) has been reached. In summary, KCNC1 is definitively associated with autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0014521
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KCNC1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001112741.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 204 | 3 | 209 | ||
| missense | 1 | 17 | 254 | 19 | 291 | |
| nonsense | 2 | 5 | 7 | |||
| start loss | 0 | |||||
| frameshift | 2 | 7 | 9 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 1 | 21 | 269 | 223 | 3 | 517 |
Highest pathogenic variant AF is 0.0000064389287
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001106212.1 | 4 | MANE Select | |
| Ensembl | ENSP00000265969.7 | 4 | MANE Select | |
| RefSeq | NP_004967.1 | 2 | Standard | |
| Ensembl | ENSP00000368785.3 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Neuronal System
- Voltage gated Potassium channels
- Potassium Channels
Biological Process
- potassium ion transport
- response to toxic substance
- response to light intensity
- response to auditory stimulus
- response to amine
Molecular Function
- voltage-gated potassium channel activity
- delayed rectifier potassium channel activity
- kinesin binding
- ion channel binding
- voltage-gated ion channel activity involved in regulation of presynaptic membrane potential
Cellular Component
- plasma membrane
- voltage-gated potassium channel complex
- cell surface
- integral component of membrane
- axon
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000265969
- Coding exons
- 4
- Length
- 48244
- Individuals with no LoFs
- 124714
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 124717
- p
- 0.0000120
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.52 | 139 | 390 | 0.356 | 0.0000267 | 3802 |
| Missense (PolyPhen) | 35 | 190.68 | 0.18356 | 1879 | ||
| Synonymous | 1.28 | 159 | 181 | 0.879 | 0.0000145 | 1201 |
| Loss of Function | 3.73 | 1 | 18.1 | 0.0551 | 8.67e-7 | 209 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Voltage-gated potassium channel that plays an important role in the rapid repolarization of fast-firing brain neurons. The channel opens in response to the voltage difference across the membrane, forming a potassium-selective channel through which potassium ions pass in accordance with their electrochemical gradient (PubMed:25401298). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNC2, and possibly other family members as well. Contributes to fire sustained trains of very brief action potentials at high frequency in pallidal neurons. {ECO:0000250|UniProtKB:P25122, ECO:0000269|PubMed:25401298}.;
- Disease
- DISEASE: Epilepsy, progressive myoclonic 7 (EPM7) [MIM:616187]: A neurologic disorder characterized by progressive myoclonic epilepsy, manifesting in the first or second decades of life. Cognitive function may decline in some patients. Myoclonus is a brief, involuntary twitching of a muscle or a group of muscles. {ECO:0000269|PubMed:25401298}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.177
Intolerance Scores
- LoFtool
- 0.0102
- RVIS EVS
- -0.67
- RVIS percentile EVS
- 15.62
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.732
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |