KCNE2

Summary

KCNE2 (potassium voltage-gated channel subfamily E regulatory subunit 2, HGNC:6242) is a protein-coding gene on chromosome 21q22.11, encoding Potassium voltage-gated channel subfamily E member 2 (Q9Y6J6). Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits.

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.

Source: NCBI Gene 9992 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial atrial fibrillation (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 22
• Clinical variants (ClinVar): 117 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 33
• MANE Select transcript: NM_172201

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6242
Approved symbol	KCNE2
Name	potassium voltage-gated channel subfamily E regulatory subunit 2
Location	21q22.11
Locus type	gene with protein product
Status	Approved
Aliases	MiRP1, LQT6
Ensembl gene	ENSG00000159197
Ensembl biotype	protein_coding
OMIM	603796
Entrez	9992

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000290310, ENST00000715813

RefSeq mRNA: 1 — MANE Select: NM_172201 NM_172201

CCDS: CCDS13635

Canonical transcript exons

ENST00000290310 — 2 exons

Exon	Start	End
ENSE00004028009	34364006	34364151
ENSE00004028014	34370467	34371381

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 91.17.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1009 / max 154.8561, expressed in 6 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188931	0.1009	6

Top tissues by expression

282 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
body of stomach	UBERON:0001161	91.17	gold quality
pylorus	UBERON:0001166	90.34	gold quality
cardia of stomach	UBERON:0001162	90.27	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.26	gold quality
stomach	UBERON:0000945	89.83	gold quality
fundus of stomach	UBERON:0001160	86.74	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.31	gold quality
sperm	CL:0000019	78.18	gold quality
male germ cell	CL:0000015	75.86	gold quality
buccal mucosa cell	CL:0002336	72.52	gold quality
oocyte	CL:0000023	72.29	gold quality
diaphragm	UBERON:0001103	68.34	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	68.22	gold quality
descending thoracic aorta	UBERON:0002345	67.63	gold quality
duodenum	UBERON:0002114	67.58	gold quality
popliteal artery	UBERON:0002250	67.04	gold quality
tibial artery	UBERON:0007610	67.04	gold quality
aorta	UBERON:0000947	66.47	gold quality
right coronary artery	UBERON:0001625	66.24	gold quality
thoracic aorta	UBERON:0001515	65.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	65.82	gold quality
ascending aorta	UBERON:0001496	65.63	gold quality
biceps brachii	UBERON:0001507	65.58	gold quality
metanephros cortex	UBERON:0010533	65.30	gold quality
decidua	UBERON:0002450	64.49	gold quality
ventricular zone	UBERON:0003053	64.37	gold quality
orbitofrontal cortex	UBERON:0004167	64.37	gold quality
secondary oocyte	CL:0000655	64.02	gold quality
right testis	UBERON:0004534	63.91	gold quality
vastus lateralis	UBERON:0001379	63.89	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting KCNE2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-34B-3P	98.70	67.40	1171
HSA-MIR-3152-5P	96.98	66.88	819
HSA-MIR-5186	94.63	66.76	627

Literature-anchored findings (GeneRIF, showing 38)

• The accelerated inactivation time course of HERG/MiRP1(V65M) channels may decrease I(Kr) current density of myocardial cells, thereby impairing the ability of myocytes to repolarize in response to sudden membrane depolarizations such as extrasystoles. (PMID:12185453)
• KCNE2, by modulating I(f) or I(h) currents, might thus contribute to the electrophysiological diversity of known pacemaking currents in the heart and brain (PMID:12856183)
• Most significant effects of MiRP1 subunits on HERG channels were more negative steady-state activation for HERG + T8A MiRP1 and more positive steady-state activation for HERG + M54T MiRP1 compared to either HERG + WT MiRP1 or HERG alone. (PMID:12923204)
• KCNE2 protein is expressed in ventricles, and it can play diverse roles in ventricular electrical activity under (patho)physiological conditions. (PMID:15066947)
• KCNE2 R27C is a gain-of-function mutation associated with the initiation and/or maintenance of Atrial Fibrillation. (PMID:15368194)
• These results suggest that KCNE2 can functionally couple to KCNQ1 even in the presence of KCNE1. (PMID:16631607)
• We demonstrated that 9.5% of cases diagnosed as SIDS carry functionally significant genetic variants in LQTS genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CAV3). (PMID:17210839)
• External pH can modify current amplitude and biophysical properties of KCNQ1. KCNE subunits work as molecular switches by modulating the pH sensitivity of human KCNQ1. (PMID:17310097)
• We propose that the KCNE2 TMD adopts an alpha-helical secondary structure with one face making intimate contact with the KCNQ1 pore domain, while the contacts with the KCNQ1 voltage-sensing domain appear more dynamic. (PMID:17676362)
• Results suggest that during biogenesis of channels HERG is more likely to assemble with KCNE1 than KCNE2 due to distinctly different trafficking rates and retention in the cell rather than differences in relative affinity. (PMID:17895974)
• results show that MiRP1 is largely alpha helical and that the predicted transmembrane and intracellular domains in particular require extensive hydrophobic interaction for adoption of ordered, non-aggeegated structure (PMID:18221016)
• KChIP2c and KCNE2 simultaneously participate in recapitulation of the electrophysiological properties of transient outward current in cardiac myocytes (PMID:18501111)
• KCNE variants reveal a critical role of the beta subunit carboxyl terminus in PKA-dependent regulation of the IKs potassium channel, KCNQ1. (PMID:19077539)
• Human MiRP1 slowed Kv2.1 activation and deactivation twofold. Compared to wild-type human MiRP1-Kv2.1 complexes, channels formed with M54T- or I57T-MiRP1 showed greatly slowed activation (tenfold and fivefold, respectively). (PMID:19219384)
• in cardiac myocytes the IKs current amplitude is under dynamic control by the availability of KCNE2 subunits in the cell membrane (PMID:19372218)
• KCNE2 plays a role in normal function of native I(to) channel complex in human heart, M54T and I57T variants lead to gain of function of I(to), contributing to generating potential arrhythmogeneity and pathogenesis for inherited fatal rhythm disorders. (PMID:20042375)
• Results suggest KCNE2 disruption as a possible risk factor for gastric neoplasia. (PMID:20625512)
• Backbone assignments of most MiRP1 residues were achieved through a series of triple resonance NMR experiments. (PMID:21087668)
• The known interactions of the KCNE2 protein and the resulting functional effects, the effects of mutations in KCNE2 and their clinical role are discussed. [review] (PMID:22166675)
• KCNE2 can modulate its partner channel function not only by altering channel conductance and/or gating kinetics, but also by affecting protein stability. (PMID:22180649)
• Case Report: reduced expression of KCNE2 in surgically excised tissue from human gastric cancer associated with gastritis cystica profunda. (PMID:23483772)
• KCNE1 and KCNE2, auxiliary subunits of voltage-gated potassium channels, undergo sequential cleavage mediated by either alpha-secretase and presenilin(PS)/gamma-secretase or BACE1 and PS/gamma-secretase in cells. (PMID:23504710)
• Subjects with LQT-PM may have longer QTc intervals at rest and at peak exercise and all phases of the recovery period compared to controls. Those with homozygous SNPs (KCNE2 1%) had longer resting QTc intervals when compared to heterozygotes. (PMID:23714088)
• study concluded that the variants in KCNQ1, KCNH2, KCNE1 and KCNE2 genes may be correlated with the occurrence of part of sudden unexplained nocturnal death syndrome cases in southern China (PMID:23890619)
• Mutations in KCNE2 has been shown to cause familial atrial fibrillation. (PMID:24460807)
• M54T MiRP1 mutation axecerbate drug-induced long QT syndrome and arrhythmia. (PMID:24631769)
• The effect of KCNE2 mutations on KV7.1 was abolished in the presence of the major IKs beta-subunit KCNE1, when coexpressed in a 1:1:1 molar ratio. (PMID:24796621)
• The transmembrane domains (TMDs) of KCNE1 and KCNE2 were illustrated to associate with the KCNQ1 channel in different modes. (PMID:24827085)
• Women with elevated BMI have enhanced hERG activity as a result of low beta-inhibitory protein expression, which likely contributes to weak contractions and poor labour outcomes. (PMID:24937480)
• KCNE2 has been widely studied since its role in the heart was discovered; it is association with inherited and acquired human Long QT syndrome; physiological analyses together with genetics studies have uncovered a startling array of functions for KCNE2, in the heart, stomach, thyroid and choroid plexus. [Review] (PMID:26123744)
• The identification of Filamin C as a novel KCNE2 ligand not only enhances current understanding of ion channel function and regulation, but also provides valuable information about possible pathways likely to be involved in long-QT syndrome pathogenesis (PMID:26956495)
• These results demonstrate that KCNE2 is required for normal beta-cell electrical activity and insulin secretion, and that Kcne2 deletion causes T2DM. (PMID:28280005)
• On the basis of clinical phenotype, the high allelic frequencies of LQT6 mutations in the Exome Aggregation Consortium database, and absence of previous documentation of genotype-phenotype segregation, our findings suggest that many KCNE2 variants, and perhaps all, have been erroneously designated as LQTS-causative mutations. Instead, KCNE2 variants may confer proarrhythmic susceptibility when provoked by additional envir (PMID:28794082)
• In vitro functional assays showed miR-584-5p depletion decreased HCC cell proliferation, cell migration, and cell invasion. Moreover, miR-584-5p functions by directly targeting KCNE2, and it in turn, mediates the effects of miR-584-5p on HCC cell behaviors. (PMID:31044566)
• KCNE2 rs8134775 was associated with a decreased atrial fibrillation (AF) risk in the Chinese Han population in the allele model. Minor allele T of GJA5 rs35594137 was associated with a decreased AF risk, and the minor allele G of KCNJ2 rs8079702 was associated with an increased AF risk in the recessive models. Results suggest that KCNE2, KCNJ2, and GJA5 influence the development of AF in the Chinese Han population. (PMID:31270966)
• An arginine/lysine-based motif (R/K[R/K][R/K]) in the proximal C-terminus regulating the endoplasmic reticulum (ER) export of KCNE1 and KCNE2. (PMID:31679457)
• The focal adhesion protein Testin modulates KCNE2 potassium channel beta subunit activity. (PMID:33464998)
• The Multifunctional Role of KCNE2: From Cardiac Arrhythmia to Multisystem Disorders. (PMID:39272981)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Kcne2	ENSMUSG00000039672
rattus_norvegicus	Kcne2	ENSRNOG00000029811

Paralogs (1): KCNE1 (ENSG00000180509)

Protein

Protein identifiers

Potassium voltage-gated channel subfamily E member 2 — Q9Y6J6 (reviewed: Q9Y6J6)

Alternative names: MinK-related peptide 1, Minimum potassium ion channel-related peptide 1, Potassium channel subunit beta MiRP1

All UniProt accessions (1): Q9Y6J6

UniProt curated annotations — full annotation on UniProt →

Function. Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits. KCNE2 beta subunit modulates the gating kinetics and enhances stability of the channel complex. Alters the gating of the delayed rectifier Kv channel containing KCNB1 alpha subunit. Associates with KCNH2/HERG alpha subunit Kv channel to form the rapidly activating component of the delayed rectifying potassium current (IKr) in heart. May associate with KCNQ2 and/or KCNQ3 alpha subunits to modulate the native M-type current. May associate with HCN1 and HCN2 channel subunits to increase potassium current. Forms a heterooligomer complex with KCNQ1/KVLQT1 alpha subunits which leads 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. KCNQ1-KCNE2 channel associates with Na(+)-coupled myo-inositol symporter in the apical membrane of choroid plexus epithelium and regulates the myo-inositol gradient between blood and cerebrospinal fluid with an impact on neuron excitability.

Subunit / interactions. Interacts with KCNB1. Associates with KCNH2/ERG1. May associate with KCNQ2 and KCNQ3. Associates with HCN1 and probably HCN2. Heteromultimer with KCNC2. Interacts with KCNC2. Interacts with KCNQ1; forms a heterooligomer complex that targets to the membrane raft and 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.

Subcellular location. Cell membrane. Apical cell membrane.

Tissue specificity. Highly expressed in brain, heart, skeletal muscle, pancreas, placenta, kidney, colon and thymus. A small but significant expression is found in liver, ovary, testis, prostate, small intestine and leukocytes. Very low expression, nearly undetectable, in lung and spleen.

Disease relevance. Long QT syndrome 6 (LQT6) [MIM:613693] A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the potassium channel KCNE family.

RefSeq proteins (1): NP_751951* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000369	K_chnl_KCNE	Family
IPR005425	K_chnl_volt-dep_bsu_KCNE2	Family

Pfam: PF02060

UniProt features (25 total): sequence variant 16, helix 3, glycosylation site 2, chain 1, transmembrane region 1, topological domain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2M0Q	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6J6-F1	78.41	0.31

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (2): 6, 29

Mutagenesis-validated functional residues (1):

Position	Phenotype
75	increases tail current in kcnh2/kcne2 channel.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5576890	Phase 3 - rapid repolarisation
R-HSA-5576893	Phase 2 - plateau phase
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction

MSigDB gene sets: 203 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOCC_CELL_SURFACE, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CELL_MEMBRANE_REPOLARIZATION, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_POTASSIUM_ION_TRANSPORT, GOBP_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HEART_RATE

GO Biological Process (18): regulation of membrane repolarization (GO:0060306), regulation of ventricular cardiac muscle cell membrane repolarization (GO:0060307), cellular response to xenobiotic stimulus (GO:0071466), potassium ion transmembrane transport (GO:0071805), cardiac muscle cell action potential involved in contraction (GO:0086002), ventricular cardiac muscle cell action potential (GO:0086005), membrane repolarization (GO:0086009), membrane repolarization during action potential (GO:0086011), regulation of heart rate by cardiac conduction (GO:0086091), potassium ion export across plasma membrane (GO:0097623), membrane repolarization during ventricular cardiac muscle cell action potential (GO:0098915), regulation of potassium ion transmembrane transport (GO:1901379), positive regulation of proteasomal protein catabolic process (GO:1901800), negative regulation of delayed rectifier potassium channel activity (GO:1902260), potassium ion import across plasma membrane (GO:1990573), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (8): potassium channel regulator activity (GO:0015459), transmembrane transporter binding (GO:0044325), voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization (GO:1902282), inward rectifier potassium channel activity (GO:0005242), voltage-gated potassium channel activity (GO:0005249), delayed rectifier potassium channel activity (GO:0005251), potassium channel activity (GO:0005267), protein binding (GO:0005515)

GO Cellular Component (7): lysosome (GO:0005764), plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), cell surface (GO:0009986), apical plasma membrane (GO:0016324), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cardiac conduction	2
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
potassium ion transmembrane transport	3
regulation of membrane potential	2
membrane repolarization	2
ventricular cardiac muscle cell membrane repolarization	2
potassium channel activity	2
voltage-gated potassium channel activity	2
cellular anatomical structure	2
regulation of biological process	1
regulation of cardiac muscle cell membrane repolarization	1
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
cardiac muscle cell action potential	1
cardiac muscle cell contraction	1
cardiac muscle cell action potential involved in contraction	1
action potential	1
regulation of heart rate	1
cardiac conduction	1
export across plasma membrane	1
ventricular cardiac muscle cell action potential	1
membrane repolarization during cardiac muscle cell action potential	1
regulation of potassium ion transport	1
regulation of monoatomic cation transmembrane transport	1
proteasomal protein catabolic process	1
positive regulation of protein catabolic process	1
regulation of proteasomal protein catabolic process	1
delayed rectifier potassium channel activity	1
regulation of delayed rectifier potassium channel activity	1
negative regulation of voltage-gated potassium channel activity	1
inorganic cation import across plasma membrane	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
ion channel regulator activity	1
protein binding	1
voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization	1
membrane repolarization during ventricular cardiac muscle cell action potential	1
ligand-gated monoatomic cation channel activity	1

Protein interactions and networks

STRING

738 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNE2	KCNQ1	P51787	999
KCNE2	KCNH2	Q12809	997
KCNE2	SCN5A	Q14524	977
KCNE2	KCNE3	Q9Y6H6	965
KCNE2	KCNJ2	P48049	889
KCNE2	KCNE4	Q8WWG9	887
KCNE2	SCN4B	Q8IWT1	881
KCNE2	KCNA5	P22460	872
KCNE2	AKAP9	Q99996	870
KCNE2	CACNA1C	Q13936	840
KCNE2	KCND2	Q9NZV8	839
KCNE2	SNTA1	Q13424	806
KCNE2	KCNJ5	P48544	803
KCNE2	CAV3	P56539	792
KCNE2	KCNE5	Q9UJ90	791

IntAct

0 interactions, top by confidence:

BioGRID (11): KCNE2 (Affinity Capture-Western), KCNE2 (Reconstituted Complex), KCNE2 (FRET), CACNA1C (Affinity Capture-Western), KCNE2 (Reconstituted Complex), KCNE2 (Two-hybrid), KCNE2 (Two-hybrid), KCNE2 (Positive Genetic), KCNE2 (Co-fractionation), KCNE2 (Co-fractionation), KCNE2 (Affinity Capture-Western)

ESM2 similar proteins: A0A1B0GST9, A0A1B0GTU2, A0A1B0GV90, A0A590UK83, A2RRL7, A7S641, A8WG88, A9JTJ0, B9X187, K7EJ46, O00168, O08589, O13001, P0C2S0, P15383, P41237, P56513, P60606, P63160, P63161, Q04645, Q04646, Q04679, Q04680, Q0P467, Q28EH9, Q3SZX0, Q3UJ81, Q3URE8, Q3ZBP2, Q4LDR2, Q4R6L9, Q502I1, Q592E4, Q5XF36, Q6AXF6, Q6NWH5, Q6PBK8, Q6Q3F5, Q71RC9

Diamond homologs: P15382, P15383, P23299, P63160, P63161, Q28705, Q5R8Q2, Q60409, Q9BDR0, Q9D808, Q9TUH9, Q9WTW3, Q9XSP1, Q9Y6J6, Q8WWG9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

117 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	61
Likely benign	24
Benign	9

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1072405	NC_000021.8:g.35742772-?_36421202+?del	Pathogenic
6056	NM_172201.2(KCNE2):c.178T>C (p.Phe60Leu)	Pathogenic
812914	NC_000021.8:g.35304355_36865958del	Likely pathogenic

SpliceAI

308 predictions. Top by Δscore:

Variant	Effect	Δscore
21:34364149:TAGGT:T	donor_loss	1.0000
21:34364150:AGGT:A	donor_loss	1.0000
21:34364152:G:GG	donor_gain	1.0000
21:34364153:T:A	donor_loss	1.0000
21:34364147:CATAG:C	donor_gain	0.9900
21:34364148:ATAG:A	donor_gain	0.9900
21:34364149:TAG:T	donor_gain	0.9900
21:34364150:AG:A	donor_gain	0.9900
21:34364151:GG:G	donor_gain	0.9900
21:34370459:A:G	acceptor_gain	0.9900
21:34370466:GC:G	acceptor_gain	0.9900
21:34370458:A:AG	acceptor_gain	0.9800
21:34370465:A:AG	acceptor_gain	0.9800
21:34370465:AGCAG:A	acceptor_gain	0.9800
21:34370466:G:GG	acceptor_gain	0.9800
21:34370466:GCA:G	acceptor_gain	0.9800
21:34370466:GCAGG:G	acceptor_gain	0.9800
21:34370458:AAATT:A	acceptor_gain	0.9700
21:34370460:A:AG	acceptor_gain	0.9600
21:34370462:TGCAG:T	acceptor_loss	0.9600
21:34370463:GCA:G	acceptor_loss	0.9600
21:34370465:A:AT	acceptor_loss	0.9600
21:34370466:G:GA	acceptor_loss	0.9600
21:34365870:T:TA	acceptor_gain	0.8900
21:34370460:ATT:A	acceptor_gain	0.8900
21:34370462:T:A	acceptor_gain	0.8900
21:34364152:G:T	donor_gain	0.8600
21:34370459:AATT:A	acceptor_gain	0.8600
21:34370461:T:G	acceptor_gain	0.8600
21:34364119:A:T	donor_gain	0.8300

AlphaMissense

823 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:34370650:G:A	G58R	0.989
21:34370650:G:C	G58R	0.989
21:34370651:G:A	G58E	0.989
21:34370636:T:C	L53P	0.982
21:34370686:A:C	S70R	0.982
21:34370688:C:A	S70R	0.982
21:34370688:C:G	S70R	0.982
21:34370681:T:C	L68P	0.976
21:34370662:T:C	F62L	0.975
21:34370664:C:A	F62L	0.975
21:34370664:C:G	F62L	0.975
21:34370654:T:G	M59R	0.972
21:34370741:T:A	I88N	0.971
21:34370654:T:A	M59K	0.969
21:34370675:C:A	A66D	0.968
21:34370681:T:G	L68R	0.966
21:34370681:T:A	L68Q	0.965
21:34370741:T:G	I88S	0.963
21:34370636:T:A	L53H	0.962
21:34370672:T:A	V65E	0.961
21:34370723:A:G	D82G	0.959
21:34370697:A:C	K73N	0.955
21:34370697:A:T	K73N	0.955
21:34370636:T:G	L53R	0.954
21:34370645:T:G	M56R	0.947
21:34370728:T:G	Y84D	0.946
21:34370659:T:C	S61P	0.945
21:34370674:G:C	A66P	0.945
21:34370703:G:C	K75N	0.943
21:34370703:G:T	K75N	0.943

dbSNP variants (sampled 300 via entrez): RS1000169822 (21:34365272 C>A,T), RS1000325022 (21:34367585 A>G,T), RS1000568514 (21:34369036 G>A,T), RS1000599558 (21:34368696 C>T), RS1000675443 (21:34367914 T>C), RS1000733677 (21:34363358 C>G,T), RS1000806355 (21:34362723 G>T), RS1002121285 (21:34368595 G>A,C), RS1002173077 (21:34367487 T>C), RS1002216132 (21:34362384 C>T), RS1002775880 (21:34366509 C>A,T), RS1003795629 (21:34367046 A>G), RS1003826820 (21:34366792 A>C), RS1004117834 (21:34368328 C>T), RS1004166888 (21:34371283 A>G)

Disease associations

OMIM: gene MIM:603796 | disease phenotypes: MIM:613693, MIM:601399, MIM:611493, MIM:192500, MIM:192600

GenCC curated gene-disease

Disease	Classification	Inheritance
familial atrial fibrillation	Supportive	Autosomal dominant
long QT syndrome 6	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
long QT syndrome	Disputed	AD

Mondo (10): long QT syndrome 6 (MONDO:0013370), hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (MONDO:0100083), atrial fibrillation, familial, 4 (MONDO:0012677), long QT syndrome (MONDO:0002442), cardiac rhythm disease (MONDO:0007263), familial long QT syndrome (MONDO:0019171), atrial fibrillation (MONDO:0004981), familial hypertrophic cardiomyopathy (MONDO:0024573), thrombocytopenia (MONDO:0002049), familial atrial fibrillation (MONDO:0018054)

Orphanet (5): Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768), Familial platelet disorder with associated myeloid malignancy (Orphanet:71290), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000365	Hearing impairment
HP:0001197	Abnormality of prenatal development or birth
HP:0001250	Seizure
HP:0001279	Syncope
HP:0001645	Sudden cardiac death
HP:0001657	Prolonged QT interval
HP:0001658	Myocardial infarction
HP:0001663	Ventricular fibrillation
HP:0001664	Torsade de pointes
HP:0001688	Sinus bradycardia
HP:0001695	Cardiac arrest
HP:0001727	Thromboembolic stroke
HP:0001907	Thromboembolism
HP:0001962	Palpitations
HP:0002094	Dyspnea
HP:0002321	Vertigo
HP:0002900	Hypokalemia
HP:0003546	Exercise intolerance
HP:0003581	Adult onset
HP:0003584	Late onset
HP:0003596	Middle age onset
HP:0004308	Ventricular arrhythmia
HP:0004754	Permanent atrial fibrillation
HP:0004757	Paroxysmal atrial fibrillation
HP:0005110	Atrial fibrillation
HP:0005135	Abnormal T-wave
HP:0005184	Prolonged QTc interval
HP:0006699	Premature atrial contractions
HP:0012332	Abnormal autonomic nervous system physiology

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000340_3	Myocardial infarction (early onset)	6.000000e-11
GCST000817_51	Height	5.000000e-12
GCST001248_1	Pulmonary function	3.000000e-08
GCST002289_15	Coronary artery disease	3.000000e-10
GCST003116_17	Coronary artery disease	1.000000e-15
GCST003117_21	Myocardial infarction	6.000000e-12
GCST003471_9	Myocardial infarction	2.000000e-13
GCST003998_10	Joint mobility (Beighton score)	2.000000e-09
GCST004185_55	Lung function (FEV1/FVC)	2.000000e-07
GCST004581_1	Body mass index (smoking years interaction)	5.000000e-06
GCST004787_71	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	3.000000e-23
GCST005275_1	Cancer	5.000000e-07
GCST006288_411	Heel bone mineral density	3.000000e-06
GCST006288_688	Heel bone mineral density	2.000000e-11
GCST006288_87	Heel bone mineral density	6.000000e-07
GCST006979_550	Heel bone mineral density	3.000000e-21
GCST007431_76	Lung function (FEV1/FVC)	9.000000e-24
GCST007692_6	Chronic obstructive pulmonary disease	4.000000e-08
GCST007990_20	Coronary artery disease	2.000000e-08
GCST008839_436	Height	4.000000e-10
GCST010479_48	Coronary artery disease	1.000000e-10
GCST010866_172	Coronary artery disease	1.000000e-16

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004713	FEV/FVC ratio
EFO:0007905	joint hypermobility measurement
EFO:0004340	body mass index
EFO:0009270	heel bone mineral density

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D001281	Atrial Fibrillation	C14.280.067.198; C23.550.073.198
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C566244	Atrial Fibrillation, Familial, 4 (supp.)
C566333	Long Qt Syndrome 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2234916	KCNE2		0.00	0
rs74315448	KCNE2		0.00	0

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression, increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Valproic Acid	affects expression, decreases methylation	2
sodium arsenite	increases expression	1
E 4031	affects binding, decreases activity, increases response to substance	1
CGP 52608	affects binding, increases reaction	1
Air Pollutants	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Dexamethasone	affects expression	1
Methylmercury Compounds	increases expression	1
Phenobarbital	increases expression	1
Potassium	increases transport, affects binding	1
Propranolol	affects binding, decreases activity	1
Rotenone	increases expression	1
Aflatoxin B1	increases methylation	1
Clarithromycin	affects binding, increases response to substance	1
Cadmium Chloride	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B5NC	PGPC14_16	Induced pluripotent stem cell	Female
CVCL_B5ND	PGPC14_26	Induced pluripotent stem cell	Female
CVCL_B5NE	PGPC14_70	Induced pluripotent stem cell	Female
CVCL_B5NF	PGPC14_94	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT00146822	PHASE4	COMPLETED	REFLEx Study (ENDOTAK RELIANCE G Evaluation of Handling and Electrical Performance
NCT00187239	PHASE4	COMPLETED	Reduce Ventricular Pacing in Dual Chamber Implantable Cardioverter Defibrillators Using AutoIntrinsic Conduction Search Study
NCT00247533	PHASE4	UNKNOWN	Cerebral Artery Stenosis, Coronary Artery Disease and Arrhythmia
NCT00282620	PHASE4	UNKNOWN	Magnesium to Reduce Implantable Cardioverter Defibrillator (ICD) Shocks and Improve Patient’s Quality of Life.
NCT00290056	PHASE4	UNKNOWN	Effect of Supplemental Intake of Omega-3 Polyunsaturated Fatty Acids on the Rate and Complexity of Spontaneously Occurring Ventricular and Supraventricular Arrhythmias in Patients With Implantable Cardioverter Defibrillator (ICD) - A Randomized Clinical Trial
NCT00313443	PHASE4	COMPLETED	Concentrations of Amiodarone in Fat Tissue During Chronic Treatment
NCT00457340	PHASE4	COMPLETED	Atorvastatin For The Reduction Of Ventricular Arrhythmias
NCT00507390	PHASE4	WITHDRAWN	Omega 3 Polyunsaturated Fatty Acid Supplements (PUFAs) and Microvolt T Wave Alternans (TWA) in Patients With Ventricular Arrhythmia
NCT00575523	PHASE4	COMPLETED	Atropine for Prevention of Dysrhythmias Caused by Percutaneous Ethanol Instillation for Hepatoma Therapy
NCT00579098	PHASE4	COMPLETED	The Use of Statins Following a Left Atrial Catheter Ablation Procedure to Prevent Atrial Fibrillation
NCT01613092	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01628666	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01717469	PHASE4	UNKNOWN	Safety and the Effects of Isolated Left Ventricular Pacing in Patients With Bradyarrhythmias
NCT01819064	PHASE4	COMPLETED	Heart Rate Response to Atropine Doses Less Than 0.1mg IV to Anesthetized Infants
NCT01834872	PHASE4	UNKNOWN	Safety and Feasibility of Arrhythmia Ablation Using the Amigo Remote Robotic System as Compared With Manual Ablation
NCT01841242	PHASE4	COMPLETED	Comparison of Alcoholic Chlorhexidine 2% Versus Alcoholic Povidone Iodine for Infections Prevention With Cardiac Resynchronization Therapy Device Implantation
NCT01991223	PHASE4	UNKNOWN	Dexmedetomidine for Catheter-related Bladder Discomfort
NCT02045173	PHASE4	COMPLETED	Automate Detection of Sleep Apnea by ApneascanTM
NCT02203630	PHASE4	TERMINATED	Phenylephrine Versus Norepinephrine for Septic Shock in Critically Ill Patients
NCT02565069	PHASE4	COMPLETED	Identification for the Treatment of Complex Arrhythmias
NCT03273634	PHASE4	COMPLETED	The Effect of Proton Pump Inhibition on Palpitations
NCT03289429	PHASE4	UNKNOWN	Antiarrhythmic and Cardioprotective Effects of Atorvastatin Versus Magnesium Sulfate in Cardiac Valve Replacement Surgery
NCT03895411	PHASE4	UNKNOWN	Efficacy and Safety of Sotalol in Children With Arrhythmia
NCT05486377	PHASE4	COMPLETED	Remimazolam vs Desflurane for General Anesthesia for Ablation of Arrhythmia
NCT06574555	PHASE4	COMPLETED	Norepinephrine ED90 Bolus After Spinal Anesthesia in Cesarean Section
NCT00000464	PHASE3	COMPLETED	Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE)
NCT00000476	PHASE3	COMPLETED	Digitalis Investigation Group (DIG)
NCT00000480	PHASE3	COMPLETED	Multicenter Unsustained Tachycardia Trial (MUSTT)
NCT00000492	PHASE3	COMPLETED	Beta-Blocker Heart Attack Trial (BHAT)
NCT00000502	PHASE3	COMPLETED	Evaluation of SC-V Versus Conventional CPR
NCT00000517	PHASE3	COMPLETED	Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF)
NCT00000518	PHASE3	COMPLETED	Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM)
NCT00000531	PHASE3	COMPLETED	Antiarrhythmics Versus Implantable Defibrillators (AVID)
NCT00000540	PHASE3	COMPLETED	Coronary Artery Bypass Graft (CABG) Patch Trial
NCT00000556	PHASE3	COMPLETED	Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM)
NCT00000561	PHASE3	COMPLETED	Mode Selection Trial in Sinus Node Dysfunction (MOST)