KCNE2

Chr 21AD

potassium voltage-gated channel subfamily E regulatory subunit 2

Also known as: ATFB4, LQT5, LQT6, MIRP1

NCBI Gene: 9992 ENSG00000159197 UniProt: Q9Y6J6 OMIM: 603796

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]

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.942 OMIM phenotypes

Clinical Summary— KCNE2

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Gene-Disease Validity (ClinGen)

long QT syndrome · ADDisputed

Disputed — evidence questions this relationship

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 90 VUS of 172 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.94LOEUF

pLI 0.000

Z-score -0.95

OE 1.57 (0.73–1.94)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.11Z-score

OE missense 0.96 (0.79–1.18)

68 obs / 70.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.57 (0.73–1.94)

0≤0.351.4

Missense OE?0.96 (0.79–1.18)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 5 / 3.2Missense obs/exp: 68 / 70.7Syn Z: -0.06

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedKCNE2-related long QT syndromeOTHERAD

This gene — mechanism propensity

0.78top 25%

GOF

0.83top 5%

LOF

0.1895th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFIdentification of a KCNE2 Gain-of-Function Mutation in Patients with Familial Atrial Fibrillation1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 15368194 ↗

ClinVar Variant Classifications

172 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS90

Likely Benign43

Benign10

Conflicting23

Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	1	0	2
Likely Pathogenic	0	0	0	0	0
VUS	10	68	12	0	90
Likely Benign	0	3	4	36	43
Benign	0	0	10	0	10
Conflicting	—				23
Total	10	72	27	36	168

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

63 pathogenic / likely-pathogenic (of 80) ClinVar copy-number / structural variants overlap KCNE2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →