KCNE2

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

Basic information

Region (hg38): 21:34364005-34371381

Links

ENSG00000159197 ∙ NCBI:9992 ∙ OMIM:603796 ∙ HGNC:6242 ∙ Uniprot:Q9Y6J6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• familial atrial fibrillation (Supportive), mode of inheritance: AD
• long QT syndrome 6 (Limited), mode of inheritance: AD
• long QT syndrome (Disputed Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Long QT syndrome 6; Atrial fibrillation, familial 4	AD	Cardiovascular; Pharmacogenomic	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)	Cardiovascular	10219239; 10973849; 15368194; 15840476; 16922724; 20301308; 20809527
Digenic/complex inheritance has been reported

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KCNE2 gene.

• Long QT syndrome 6 (88 variants)
• Cardiovascular phenotype (59 variants)
• not provided (47 variants)
• Congenital long QT syndrome (18 variants)
• Atrial fibrillation, familial, 4 (17 variants)
• Long QT syndrome 6;Atrial fibrillation, familial, 4 (11 variants)
• not specified (10 variants)
• Long QT syndrome (7 variants)
• Atrial fibrillation, familial, 4;Long QT syndrome 6 (6 variants)
• Cardiac arrhythmia (2 variants)
• Atrial fibrillation (2 variants)
• KCNE2-Related Disorders (2 variants)
• Hypertrophic cardiomyopathy;Long QT syndrome (1 variants)
• Primary dilated cardiomyopathy (1 variants)
• Acquired long QT syndrome (1 variants)
• Long QT syndrome 6, acquired, susceptibility to (1 variants)
• Long QT syndrome, drug-associated (1 variants)
• Familial atrial fibrillation (1 variants)
• Long QT syndrome;Primary familial hypertrophic cardiomyopathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KCNE2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				29		29
missense		1	49	3		53
nonsense			2			2
start loss			1			1
frameshift			2			2
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region			1			1
non coding			6	3	9	18
Total	0	1	61	35	9

Highest pathogenic variant AF is 0.00000657

Variants in KCNE2

This is a list of pathogenic ClinVar variants found in the KCNE2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
21-34364043-C-T		Congenital long QT syndrome • Familial atrial fibrillation • Long QT syndrome • Long QT syndrome 6;Atrial fibrillation, familial, 4	Uncertain significance (Oct 01, 2021)
21-34364079-G-A		Atrial fibrillation, familial, 4 • Congenital long QT syndrome • Long QT syndrome 6	Conflicting classifications of pathogenicity (Jan 12, 2018)
21-34364084-C-T		Atrial fibrillation, familial, 4 • Long QT syndrome 6 • Congenital long QT syndrome	Uncertain significance (Jan 12, 2018)
21-34364085-G-A		Atrial fibrillation, familial, 4 • Long QT syndrome 6 • Congenital long QT syndrome	Benign/Likely benign (Jan 12, 2018)
21-34364112-G-A		Atrial fibrillation, familial, 4 • Long QT syndrome 6 • Congenital long QT syndrome	Conflicting classifications of pathogenicity (Jan 12, 2018)
21-34364134-T-C		not specified	Benign (Nov 17, 2014)
21-34364145-T-A			Benign (Mar 03, 2015)
21-34364156-G-A		Atrial fibrillation, familial, 4 • Congenital long QT syndrome • Long QT syndrome 6 • Atrial fibrillation, familial, 4;Long QT syndrome 6	Uncertain significance (Jul 25, 2022)
21-34364464-T-C			Likely benign (Aug 15, 2018)
21-34370411-C-T			Benign (Mar 03, 2015)
21-34370423-C-T			Benign (Mar 03, 2015)
21-34370440-T-C			Likely benign (Nov 16, 2018)
21-34370451-A-G		not specified	Benign (Mar 03, 2015)
21-34370480-T-C		Long QT syndrome 6 • Long QT syndrome 6;Atrial fibrillation, familial, 4	Uncertain significance (Aug 03, 2021)
21-34370491-T-C		not specified • Long QT syndrome 6 • Atrial fibrillation, familial, 4;Long QT syndrome 6	Uncertain significance (Oct 31, 2021)
21-34370492-C-T			Uncertain significance (Jul 25, 2019)
21-34370495-A-G		Long QT syndrome 6 • Atrial fibrillation, familial, 4 • Cardiovascular phenotype • Atrial fibrillation, familial, 4;Long QT syndrome 6	Uncertain significance (Jul 02, 2021)
21-34370500-A-G		Long QT syndrome, drug-associated • not specified • Cardiovascular phenotype • Long QT syndrome • Long QT syndrome 6	Conflicting classifications of pathogenicity (Jan 31, 2024)
21-34370501-C-A		Cardiovascular phenotype	Uncertain significance (Sep 22, 2023)
21-34370501-C-T		Cardiovascular phenotype	Uncertain significance (Aug 28, 2023)
21-34370503-C-G		Long QT syndrome 6, acquired, susceptibility to • not specified • Cardiovascular phenotype • Long QT syndrome 6 • Atrial fibrillation, familial, 4	Benign/Likely benign (Jan 31, 2024)
21-34370503-C-T		Cardiovascular phenotype	Uncertain significance (Sep 16, 2020)
21-34370504-A-T		Long QT syndrome 6	Uncertain significance (Dec 13, 2022)
21-34370507-C-T		Congenital long QT syndrome • Long QT syndrome • not specified • Long QT syndrome 6 • Long QT syndrome;Hypertrophic cardiomyopathy • Cardiovascular phenotype	Conflicting classifications of pathogenicity (Jan 04, 2024)
21-34370508-G-A		Long QT syndrome 6 • Cardiovascular phenotype	Likely benign (Jan 15, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KCNE2	protein_coding	protein_coding	ENST00000290310	1	7366

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000101	0.211	125730	0	17	125747	0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.115	68	70.7	0.962	0.00000386	819
Missense in Polyphen		20	25.163	0.79481		293
Synonymous	-0.0580	28	27.6	1.01	0.00000159	226
Loss of Function	-0.949	5	3.18	1.57	2.20e-7	29

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000322	0.000322
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000176	0.0000176
Middle Eastern	0.000163	0.000109
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

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.
• Pathway: Gastric acid secretion - Homo sapiens (human);Antiarrhythmic Pathway, Pharmacodynamics;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;Phase 2 - plateau phase;Phase 3 - rapid repolarisation;Cardiac conduction;Muscle contraction (Consensus)

Recessive Scores

• pRec: 0.111

Intolerance Scores

• loftool: 0.363
• rvis_EVS: 0.28
• rvis_percentile_EVS: 71.08

Haploinsufficiency Scores

• pHI: 0.0803
• hipred: N
• hipred_score: 0.430

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.655

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Kcne2
• Phenotype: neoplasm; hematopoietic system phenotype; immune system phenotype; digestive/alimentary phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: aging;cellular response to drug;tongue development;regulation of membrane repolarization;regulation of ventricular cardiac muscle cell membrane repolarization;potassium ion transmembrane transport;cardiac muscle cell action potential involved in contraction;ventricular cardiac muscle cell action potential;membrane repolarization;membrane repolarization during action potential;regulation of heart rate by cardiac conduction;potassium ion export across plasma membrane;membrane repolarization during ventricular cardiac muscle cell action potential;regulation of potassium ion transmembrane transport;positive regulation of voltage-gated calcium channel activity;positive regulation of proteasomal protein catabolic process;regulation of inward rectifier potassium channel activity;regulation of cyclic nucleotide-gated ion channel activity;regulation of delayed rectifier potassium channel activity;negative regulation of delayed rectifier potassium channel activity;potassium ion import across plasma membrane
• Cellular component: lysosome;endoplasmic reticulum;Golgi apparatus;plasma membrane;voltage-gated potassium channel complex;cell surface
• Molecular function: inward rectifier potassium channel activity;delayed rectifier potassium channel activity;protein binding;potassium channel regulator activity;protein homodimerization activity;ion channel binding;voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization