KCNN2

Chr 5AD

potassium calcium-activated channel subfamily N member 2

Also known as: DYT34, KCa2.2, NEDMAB, SK2, SKCA2, SKCa 2, hSK2

NCBI Gene: 3781 ENSG00000080709 UniProt: Q9H2S1 OMIM: 605879

This gene encodes a small conductance calcium-activated potassium channel that regulates neuronal excitability by mediating calcium-dependent potassium efflux and contributing to the afterhyperpolarization that follows action potentials. Mutations cause autosomal dominant dystonia 34 (myoclonic type) and neurodevelopmental disorder with variable movement or behavioral abnormalities. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.27), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Action potentials in vertebrate neurons are followed by an afterhyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. The protein encoded by this gene is activated before membrane hyperpolarization and is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. This gene is a member of the KCNN family of potassium channel genes. The encoded protein is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits. Alternate splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.272 OMIM phenotypes

Clinical Summary— KCNN2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

20 unique Pathogenic / Likely Pathogenic· 153 VUS of 211 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.27LOEUF

pLI 0.991

Z-score 4.05

OE 0.09 (0.04–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.29Z-score

OE missense 0.65 (0.58–0.72)

214 obs / 331.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.27)

0≤0.351.4

Missense OE?0.65 (0.58–0.72)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 2 / 22.9Missense obs/exp: 214 / 331.0Syn Z: -2.31

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateKCNN2-related neurodevelopmental disorder with or without movement disorderLOFAD

This gene — mechanism propensity

0.6549th %ile

GOF

0.76top 25%

LOF

0.64top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 50% of P/LP variants are LoF · LOEUF 0.27

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.

Literature Evidence

LOFAltogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 33242881 ↗

ClinVar Variant Classifications

211 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic11

VUS153

Likely Benign27

Benign2

Conflicting4

Pathogenic

Likely Pathogenic

153

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	3	1	0	9
Likely Pathogenic	5	5	1	0	11
VUS	10	141	2	0	153
Likely Benign	0	10	2	15	27
Benign	0	1	0	1	2
Conflicting	—				4
Total	20	160	6	16	206

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap KCNN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →