GeneBe

KCNA5

protein-coding

potassium voltage-gated channel subfamily A member 5, the group of Potassium voltage-gated channels

Gene summary

Potassium channels represent the most complex class of voltage-gated ino 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 delayed rectifier class, the function of which could restore the resting membrane potential of beta cells after depolarization and thereby contribute to the regulation of insulin secretion. This gene is intronless, and the gene is clustered with genes KCNA1 and KCNA6 on chromosome 12. Defects in this gene are a cause of familial atrial fibrillation type 7 (ATFB7). [provided by RefSeq, May 2012]

MANE transcript

NM_002234.4

Inheritance

AD

ClinVar variants

P:5U:425B:159

Top phenotype

Atrial fibrillation, familial, 7

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr12:5,043,879-5,046,788

External References & Databases

Ensembl (ENSG00000130037)NCBI Gene (3741)OMIM (176267)HGNC:6224GenCCUniProt (P22460)AlphaFoldClinVar (KCNA5)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~2.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial atrial fibrillationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018054

Submitter: Orphanet

atrial fibrillation, familial, 7LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012828

Submitter: Labcorp Genetics (formerly Invitae)

atrial fibrillation, familial, 7MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012828

Submitter: Ambry Genetics

atrial fibrillation, familial, 7MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012828

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Atrial fibrillation, familial, 7AD

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: Surveillance for and medical intervention to prevent morbidity related to atrial fibrillation may be beneficial

Refs: 16772329; 17266934; 19343045; 20638934Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNA5 variants in ClinVar

12 Conditions Cataloged
Atrial fibrillation, familial, 7Total: 505
not providedTotal: 119
Inborn genetic diseasesTotal: 93
not specifiedTotal: 70
KCNA5-related disorderTotal: 15
Pulmonary arterial hypertensionTotal: 5
Cardiac arrhythmiaTotal: 2
Brugada syndrome 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002234.4. 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.

EffectPLPVUSLBBSum
synonymous
36
clinvar
124
clinvar
3
clinvar
 163
missense
2
clinvar
1
clinvar
367
clinvar
29
clinvar
3
clinvar
 402
nonsense
1
clinvar
1
clinvar
4
clinvar
 6
start loss
2
clinvar
 2
frameshift
16
clinvar
 16
splice donor/acceptor (+/-2bp)
0
Total324251536589

Highest pathogenic variant AF is 0.0000105329555

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002234.4RefSeqNP_002225.21MANE Select
ENST00000252321.5EnsemblENSP00000252321.31MANE Select
ENST00001123233.1EnsemblENSP00000793038.11Standard
ENST00001123234.1EnsemblENSP00000793039.11Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Antiarrhythmic Pathway, Pharmacodynamics
  • Disopyramide Action Pathway
  • Procainamide (Antiarrhythmic) Action Pathway
  • Phenytoin (Antiarrhythmic) Action Pathway
  • Fosphenytoin (Antiarrhythmic) Action Pathway

Biological Process

  • response to hypoxia
  • potassium ion transport
  • Notch signaling pathway
  • response to mechanical stimulus
  • response to organic substance

Molecular Function

  • signaling receptor binding
  • voltage-gated potassium channel activity
  • delayed rectifier potassium channel activity
  • protein binding
  • outward rectifier potassium channel activity

Cellular Component

  • endoplasmic reticulum
  • Golgi apparatus
  • plasma membrane
  • integral component of plasma membrane
  • caveola

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000252321
Coding exons
1
Length
2865
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.05404013981.010.00002743936
Missense (PolyPhen)167187.70.889711883
Synonymous-1.582071801.150.00001321342
Loss of Function1.79714.30.4897.99e-7147

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

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. 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:12130714). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (PubMed:12130714). Homotetrameric channels display rapid activation and slow inactivation (PubMed:8505626, PubMed:12130714). May play a role in regulating the secretion of insulin in normal pancreatic islets. Isoform 2 exhibits a voltage-dependent recovery from inactivation and an excessive cumulative inactivation (PubMed:11524461). {ECO:0000269|PubMed:11524461, ECO:0000269|PubMed:12130714, ECO:0000269|PubMed:8505626}.;
Disease
DISEASE: Atrial fibrillation, familial, 7 (ATFB7) [MIM:612240]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:16772329}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.206

Intolerance Scores

LoFtool
0.0940
RVIS EVS
0.8
RVIS percentile EVS
87.59

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.843

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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