GeneBe

KCNC3

protein-coding

potassium voltage-gated channel subfamily C member 3, the group of Potassium voltage-gated channels

Gene summary

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. Alternate splicing results in several transcript variants. [provided by RefSeq, Mar 2014]

Previous symbols:
  • SCA13

MANE transcript

NM_004977.3

Inheritance

AD

ClinVar variants

P:11U:270B:174

Top phenotype

Spinocerebellar ataxia 13

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr19:50,311,937-50,333,515

External References & Databases

Ensembl (ENSG00000131398)NCBI Gene (3748)OMIM (176264)HGNC:6235GenCCUniProt (Q14003)AlphaFoldClinVar (KCNC3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~21.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia type 13STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011529

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia type 13SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011529

Submitter: Orphanet

spinocerebellar ataxia type 13STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011529

Submitter: PanelApp Australia

spinocerebellar ataxia type 13STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011529

Submitter: G2P

spinocerebellar ataxia type 13STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011529

Submitter: Genomics England PanelApp

spinocerebellar ataxia type 13DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011529

Submitter: ClinGen

The *KCNC3* gene, located on chromosome 19 at 19q13.33, encodes the potassium voltage-gated channel subfamily C member 3 (KCNC3), which plays an important role in regulation of the action potential and the rapid repolarization of fast-firing brain neurons. *KCNC3* was first reported in relation to autosomal dominant spinocerebellar ataxia 13 in 2006 (Waters et al., PMID: 16501573). Spinocerebellar ataxia 13 is characterized by slowly progressive gait and limb ataxia and dysarthria, with other variable features including intellectual impairment, oculomotor disturbances, and pyramidal signs. Twelve missense variants that have been reported in 18 probands from 8 publications (PMIDs: 16501573, 19953606, 25981959, 25756792, ​​28444220, 29482223, 31907387, 33446253) are included in this curation. Variants in this gene segregated with disease in at least 17 additional family members (PMID: 16501573). Of note, an autosomal recessive case with a homozygous missense variant has been reported in one proband (PMID: 38374194).This gene-disease relationship is also supported by experimental evidence such as a cell culture model, two zebrafish models, and rescue in a knockout mouse (PMIDs: 24218544, 20712895, 21543613, 18448641). In summary, there is definitive evidence to support the relationship between *KCNC3* and autosomal dominant spinocerebellar ataxia 13. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on the meeting date November 7th, 2024 (SOP Version 11).

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 13AD

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

Refs: 16501573Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNC3 variants in ClinVar

10 Conditions Cataloged
not providedTotal: 369
Inborn genetic diseasesTotal: 113
not specifiedTotal: 89
Spinocerebellar ataxia type 13Total: 49
KCNC3-related disorderTotal: 11
Tip-toe gaitTotal: 3
Cleft palateTotal: 1
KCNC3-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004977.3. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
138
clinvar
3
clinvar
 144
missense
5
clinvar
4
clinvar
249
clinvar
33
clinvar
 291
nonsense
1
clinvar
3
clinvar
 4
start loss
2
clinvar
 2
frameshift
1
clinvar
10
clinvar
 11
splice donor/acceptor (+/-2bp)
3
clinvar
 3
Total652701713455

Highest pathogenic variant AF is 0.0000068185086

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004977.3RefSeqNP_004968.24MANE Select
ENST00000477616.2EnsemblENSP00000434241.14MANE Select
NM_001372305.1RefSeqNP_001359234.14Standard
ENST00000376959.6EnsemblENSP00000366158.24Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • VEGFA-VEGFR2 Signaling Pathway
  • Neuronal System
  • Voltage gated Potassium channels
  • Potassium Channels

Biological Process

  • regulation of ion transmembrane transport
  • protein homooligomerization
  • protein tetramerization
  • potassium ion transmembrane transport

Molecular Function

  • voltage-gated potassium channel activity
  • delayed rectifier potassium channel activity

Cellular Component

  • cytoskeleton
  • plasma membrane
  • cell cortex
  • voltage-gated potassium channel complex
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000477616
Coding exons
4
Length
21579
Individuals with no LoFs
125688
Homozygous LoFs
0
Heterozygous LoFs
17
Defined
125705
p
0.0000676
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.042243940.5690.00002544831
Missense (PolyPhen)731860.392481937
Synonymous-0.2761881831.030.00001301686
Loss of Function2.72415.60.2578.44e-7211

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000720.000070rare
South Asian0.0000980.000098rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

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. The channel displays rapid activation and inactivation kinetics (PubMed:10712820, PubMed:26997484, PubMed:22289912, PubMed:23734863, PubMed:16501573, PubMed:19953606, PubMed:21479265, PubMed:25756792). It plays a role in the regulation of the frequency, shape and duration of action potentials in Purkinje cells. Required for normal survival of cerebellar neurons, probably via its role in regulating the duration and frequency of action potentials that in turn regulate the activity of voltage-gated Ca(2+) channels and cellular Ca(2+) homeostasis (By similarity). Required for normal motor function (PubMed:23734863, PubMed:16501573, PubMed:19953606, PubMed:21479265, PubMed:25756792). Plays a role in the reorganization of the cortical actin cytoskeleton and the formation of actin veil structures in neuronal growth cones via its interaction with HAX1 and the Arp2/3 complex (PubMed:26997484). {ECO:0000250|UniProtKB:Q63959, ECO:0000269|PubMed:10712820, ECO:0000269|PubMed:16501573, ECO:0000269|PubMed:19953606, ECO:0000269|PubMed:21479265, ECO:0000269|PubMed:22289912, ECO:0000269|PubMed:23734863, ECO:0000269|PubMed:25756792, ECO:0000269|PubMed:26997484}.;
Disease
DISEASE: Spinocerebellar ataxia 13 (SCA13) [MIM:605259]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA13 is an autosomal dominant cerebellar ataxia (ADCA) characterized by slow progression and variable age at onset, ranging from childhood to late adulthood. Mental retardation can be present in some patients. {ECO:0000269|PubMed:16501573, ECO:0000269|PubMed:19953606, ECO:0000269|PubMed:21479265, ECO:0000269|PubMed:22289912, ECO:0000269|PubMed:23734863, ECO:0000269|PubMed:25152487, ECO:0000269|PubMed:25756792}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.178

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.731

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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