GeneBe

KCNE2

protein-coding

potassium voltage-gated channel subfamily E regulatory subunit 2, the group of Potassium voltage-gated channel regulatory subunits

Gene summary

Voltage-gated potassium (Kv) 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. This gene encodes a member of the potassium channel, voltage-gated, isk-related subfamily. This member is a small integral membrane subunit that assembles with the KCNH2 gene product, a pore-forming protein, to alter its function. This gene is expressed in heart and muscle and the gene mutations are associated with cardiac arrhythmia. [provided by RefSeq, Jul 2008]

MANE transcript

NM_172201.2

Inheritance

AD

ClinVar variants

P:3U:88B:54

Top phenotype

Long QT syndrome 6; Atrial fibrillation, familial 4

gnomAD constraint

pLI —, LoF o/e 1.57

Max pathogenic AF

—

Genomic locus

chr21:34,180,729-34,371,381

External References & Databases

Ensembl (ENSG00000159197)NCBI Gene (9992)OMIM (603796)HGNC:6242GenCCUniProt (Q9Y6J6)AlphaFoldClinVar (KCNE2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~190.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

long QT syndrome 6LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013370

Submitter: Labcorp Genetics (formerly Invitae)

long QT syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0002442

Submitter: ClinGen

KCNE2 encodes the beta-subunit of voltage-gated potassium channels and is thought to assemble with KCNH2 to form Ikr (the rapidly activating delayed rectifier cardiac potassium channel). There is strong evidence associating KCNE2 with acquired LQTS, however, KCNE2 variants reported for LQTS routinely require secondary provocation to induce phenotype, persuading the Expert Panel to conclude that KCNE2 has no supportive evidence as a cause of LQTS in the absence of provoking factors (PMID 28794082). Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams were reviewed by the LQTS Clinical Domain Expert Panel. For a detailed discussion of this group's work and the separate scores of the 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”

long QT syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0002442

Submitter: G2P

familial atrial fibrillationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018054

Submitter: Orphanet

Clinical Genomic Database (CGD)

Long QT syndrome 6; Atrial fibrillation, familial 4AD

Manifestation: Cardiovascular

Intervention: Cardiovascular; Pharmacogenomic

Rationale: In Long QT syndrome, in order to prevent sequelae including syncope, cardiac arrest and sudden death prophylactic use of beta blockers in asymptomatic individuals may be beneficial; ICD may be indicated for individuals refractory to beta-blocker treatment or with history of cardiac arrest; Agents that can contribute to prolonged QT or related dysrhythmias should be avoided, as should activities associated with high stress/intense exertion; In Atrial fibrillation, surveillance and risk awareness can allow early detection and medical treatment of disease, including related sequelae (eg, thromboembolic events)

Comments: Digenic/complex inheritance has been reported

Refs: 10219239; 10973849; 15368194; 15840476; 16922724; 20301308; 20809527Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNE2 variants in ClinVar

16 Conditions Cataloged
Long QT syndrome 6Total: 101
Cardiovascular phenotypeTotal: 92
not providedTotal: 44
Atrial fibrillation, familial, 4Total: 21
not specifiedTotal: 19
Congenital long QT syndromeTotal: 10
Long QT syndromeTotal: 7
KCNE2-related disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_172201.2. 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.

EffectPLPVUSLBBSum
synonymous
39
clinvar
1
clinvar
 40
missense
1
clinvar
2
clinvar
78
clinvar
12
clinvar
1
clinvar
 94
nonsense
2
clinvar
 2
start loss
1
clinvar
 1
frameshift
7
clinvar
1
clinvar
 8
splice donor/acceptor (+/-2bp)
0
Total1288522145

Highest pathogenic variant AF is 0.000026640893

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_172201.2RefSeqNP_751951.11MANE Select
ENST00000290310.4EnsemblENSP00000290310.21MANE Select
ENST00000715813.1EnsemblENSP00000520524.11Standard
ENST00000715813.2EnsemblENSP00000520524.11Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Gastric acid secretion - Homo sapiens (human)
  • Antiarrhythmic Pathway, Pharmacodynamics
  • Disopyramide Action Pathway
  • Procainamide (Antiarrhythmic) Action Pathway
  • Phenytoin (Antiarrhythmic) Action Pathway

Biological Process

  • aging
  • cellular response to drug
  • tongue development
  • regulation of membrane repolarization
  • regulation of ventricular cardiac muscle cell membrane repolarization

Molecular Function

  • inward rectifier potassium channel activity
  • delayed rectifier potassium channel activity
  • protein binding
  • potassium channel regulator activity
  • protein homodimerization activity

Cellular Component

  • lysosome
  • endoplasmic reticulum
  • Golgi apparatus
  • plasma membrane
  • voltage-gated potassium channel complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000290310
Coding exons
1
Length
7366
Individuals with no LoFs
125730
Homozygous LoFs
0
Heterozygous LoFs
17
Defined
125747
p
0.0000676
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.1156870.70.9620.00000386819
Missense (PolyPhen)2025.1630.79481293
Synonymous-0.05802827.61.010.00000159226
Loss of Function-0.94953.181.572.20e-729

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.000260.00026rare
Ashkenazi Jewish00.0absent
East Asian0.000160.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000180.000018rare
South Asian0.0000980.000098rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Ancillary protein that assembles as a beta subunit with a voltage-gated potassium channel complex of pore-forming alpha subunits. Modulates the gating kinetics and enhances stability of the channel complex. Assembled with KCNB1 modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1. Associated with KCNH2/HERG is proposed to form the rapidly activating component of the delayed rectifying potassium current in heart (IKr). May associate with KCNQ2 and/or KCNQ3 and modulate the native M-type current. May associate with HCN1 and HCN2 and increase potassium current. Interacts with KCNQ1; forms a heterooligomer complex leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current (PubMed:11101505). {ECO:0000250|UniProtKB:P63161, ECO:0000269|PubMed:10219239, ECO:0000269|PubMed:11101505}.;
Disease
DISEASE: Atrial fibrillation, familial, 4 (ATFB4) [MIM:611493]: 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:15368194}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.111

Intolerance Scores

LoFtool
0.363
RVIS EVS
0.28
RVIS percentile EVS
71.08

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.655

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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