KCNH6

Chr 17

potassium voltage-gated channel subfamily H member 6

Also known as: ERG-2, ERG2, HERG2, Kv11.2, hERG-2

NCBI Gene: 81033 ENSG00000173826 UniProt: Q9H252 OMIM: 608168

The protein forms the pore-forming alpha subunit of voltage-gated inwardly rectifying potassium channels that regulate neuronal excitability through unusual gating kinetics, producing small outward currents during depolarization and large inward currents during repolarization. Mutations cause neurodevelopmental disorder with seizures, microcephaly, and variable intellectual disability, inherited in an autosomal dominant pattern. The gene shows extremely low constraint against loss-of-function variants (pLI near zero), suggesting the associated disorder may not result from simple protein loss.

OMIM ResearchSummary from RefSeq, UniProt

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, subfamily H. This member is a pore-forming (alpha) subunit. Alternative splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Jul 2013]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.40

Clinical Summary— KCNH6

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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

184 VUS of 199 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?

1.40LOEUF

pLI 0.000

Z-score -0.53

OE 1.09 (0.85–1.40)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.21Z-score

OE missense 1.02 (0.96–1.09)

632 obs / 617.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.09 (0.85–1.40)

0≤0.351.4

Missense OE?1.02 (0.96–1.09)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 44 / 40.4Missense obs/exp: 632 / 617.6Syn Z: 0.00

This gene — mechanism propensity

0.75top 25%

GOF

0.83top 10%

LOF

0.3940th %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

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.

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

ClinVar Variant Classifications

199 submitted variants in ClinVar

ClinVar

Classification Summary

VUS184

Likely Benign11

Benign1

184

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	184	0	184
Likely Benign	9	2	11
Benign	0	1	1
Total	193	3	196

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap KCNH6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →