KCNA4
protein-codingpotassium voltage-gated channel subfamily A member 4, the group of Potassium voltage-gated channels
Gene summary
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the A-type potassium current class, the members of which may be important in the regulation of the fast repolarizing phase of action potentials in heart and thus may influence the duration of cardiac action potential.[provided by RefSeq, Mar 2011]
- KCNA4L
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~7.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0032656
Submitter: Ambry Genetics
Inheritance Pattern: Unknown
Disease ID:MONDO:0032656
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0032656
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Neurologic; Ophthalmologic
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 KCNA4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002233.4. 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 | 6 | 6 | ||||
| missense | 72 | 1 | 73 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 73 | 7 | 0 | 80 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002224.1 | 1 | MANE Select | |
| Ensembl | ENSP00000328511.6 | 1 | MANE Select | |
| Ensembl | ENSP00000623112.1 | 1 | Standard | |
| Ensembl | ENSP00000623112.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cortisol synthesis and secretion - Homo sapiens (human)
- Cushing,s syndrome - Homo sapiens (human)
- Neuronal System
- Voltage gated Potassium channels
- Potassium Channels
Biological Process
- potassium ion transport
- regulation of ion transmembrane transport
- protein homooligomerization
- potassium ion transmembrane transport
Molecular Function
- voltage-gated potassium channel activity
- delayed rectifier potassium channel activity
- protein binding
- potassium ion binding
Cellular Component
- plasma membrane
- integral component of plasma membrane
- voltage-gated potassium channel complex
- integral component of membrane
- axon
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000328224
- Coding exons
- 1
- Length
- 7283
- Individuals with no LoFs
- 124625
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 124628
- p
- 0.0000120
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.03 | 267 | 378 | 0.707 | 0.0000212 | 4310 |
| Missense (PolyPhen) | 71 | 163.44 | 0.4344 | 1862 | ||
| Synonymous | -1.55 | 168 | 144 | 1.16 | 0.00000763 | 1294 |
| Loss of Function | 3.58 | 1 | 16.9 | 0.0593 | 8.82e-7 | 222 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000065 | 0.000065 | rare |
| 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) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:19912772, PubMed:8495559). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:8495559). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Homotetrameric KCNA4 forms a potassium channel that opens in response to membrane depolarization, followed by rapid spontaneous channel closure (PubMed:19912772, PubMed:8495559). Likewise, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation (PubMed:17156368). {ECO:0000269|PubMed:17156368, ECO:0000269|PubMed:19912772, ECO:0000269|PubMed:8495559}.;
Recessive Scores
- pRec
- 0.150
Intolerance Scores
- RVIS EVS
- -0.54
- RVIS percentile EVS
- 20.54
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.774
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |