KCNH5

Chr 14AD

potassium voltage-gated channel subfamily H member 5

Also known as: DEE112, EAG2, H-EAG2, Kv10.2, hEAG2

NCBI Gene: 27133 ENSG00000140015 UniProt: Q8NCM2 OMIM: 605716

The protein is a voltage-gated potassium channel that functions as an outward-rectifying, noninactivating channel involved in regulating neurotransmitter release and neuronal excitability. Mutations cause developmental and epileptic encephalopathy 112 through an autosomal dominant inheritance pattern. The pathogenic mechanism involves gain-of-function effects that disrupt normal neuronal signaling.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of voltage-gated potassium channels. Members of this family have diverse functions, including regulating neurotransmitter and hormone release, cardiac function, and cell volume. This protein is an outward-rectifying, noninactivating channel. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.441 OMIM phenotype

Clinical Summary— KCNH5

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Gene-Disease Validity (ClinGen)

infantile-onset epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 422 VUS of 859 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.44LOEUF

pLI 0.020

Z-score 4.47

OE 0.27 (0.17–0.44)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.51Z-score

OE missense 0.70 (0.64–0.76)

390 obs / 556.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.27 (0.17–0.44)

0≤0.351.4

Missense OE?0.70 (0.64–0.76)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 12 / 44.0Missense obs/exp: 390 / 556.6Syn Z: 0.33

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongKCNH5-related epilepsy and epileptic encephalopathyOTHERAD

This gene — mechanism propensity

0.78top 25%

GOF

0.82top 10%

LOF

0.3355th %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 · 92% of P/LP are missense

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

859 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic6

VUS422

Likely Benign344

Benign52

Conflicting22

Pathogenic

Likely Pathogenic

422

VUS

344

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	5	1	0	6
Likely Pathogenic	0	6	0	0	6
VUS	32	371	15	4	422
Likely Benign	5	23	93	223	344
Benign	0	30	13	9	52
Conflicting	—				22
Total	37	435	122	236	852

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap KCNH5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →