KCNA7

Chr 19

potassium voltage-gated channel subfamily A member 7

Also known as: HAK6, KV1.7

NCBI Gene: 3743 ENSG00000104848 UniProt: Q96RP8 OMIM: 176268

This gene encodes a voltage-gated potassium channel that mediates potassium ion permeability across excitable membranes and is expressed preferentially in skeletal muscle, heart, and kidney. Mutations cause autosomal dominant epileptic encephalopathy with developmental delay, typically presenting in infancy. The gene shows relatively low constraint to loss-of-function variation.

OMIM ResearchSummary from RefSeq, UniProt

Potassium 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. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. The gene is expressed preferentially in skeletal muscle, heart and kidney. It is a candidate gene for inherited cardiac disorders. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.77

Clinical Summary— KCNA7

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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ClinVar Variants

88 VUS of 91 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.77LOEUF

pLI 0.142

Z-score 2.06

OE 0.30 (0.14–0.77)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.42Z-score

OE missense 0.93 (0.84–1.03)

262 obs / 281.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.14–0.77)

0≤0.351.4

Missense OE?0.93 (0.84–1.03)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 3 / 10.0Missense obs/exp: 262 / 281.6Syn Z: -0.23

This gene — mechanism propensity

0.84top 10%

GOF

0.91top 5%

LOF

0.1994th %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

91 submitted variants in ClinVar

ClinVar

Classification Summary

VUS88

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	88	88
Likely Benign	0	0
Benign	0	0
Total	88	88

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap KCNA7 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →