KCNN2
protein-codingpotassium calcium-activated channel subfamily N member 2, the group of Potassium calcium-activated channels
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~440.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0859225
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0859225
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0859225
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KCNN2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_021614.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 19 | 1 | 20 | |||
| missense | 4 | 6 | 151 | 12 | 173 | |
| nonsense | 1 | 2 | 2 | 5 | ||
| start loss | 0 | |||||
| frameshift | 3 | 2 | 7 | 12 | ||
| splice donor/acceptor (+/-2bp) | 2 | 3 | 5 | |||
| Total | 8 | 12 | 163 | 31 | 1 | 215 |
Highest pathogenic variant AF is 6.9396737e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_067627.3 | 8 | MANE Select | |
| Ensembl | ENSP00000501239.1 | 8 | MANE Select | |
| RefSeq | NP_001359162.1 | 9 | Standard | |
| RefSeq | NP_740721.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Serotonergic synapse - Homo sapiens (human)
- Bile secretion - Homo sapiens (human)
- Insulin secretion - Homo sapiens (human)
- Brain-Derived Neurotrophic Factor (BDNF) signaling pathway
- Neuronal System
Biological Process
- potassium ion transport
- potassium ion transmembrane transport
- membrane repolarization during atrial cardiac muscle cell action potential
- regulation of potassium ion transmembrane transport
Molecular Function
- protein binding
- calmodulin binding
- calcium-activated potassium channel activity
- small conductance calcium-activated potassium channel activity
- protein domain specific binding
Cellular Component
- plasma membrane
- cell surface
- integral component of membrane
- Z disc
- neuron projection
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000512097
- Coding exons
- 8
- Length
- 135696
- Individuals with no LoFs
- 125674
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 17
- Defined
- 125691
- p
- 0.0000676
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.29 | 214 | 331 | 0.646 | 0.0000166 | 3772 |
| Missense (PolyPhen) | 56 | 127.92 | 0.43777 | 1556 | ||
| Synonymous | -2.31 | 166 | 132 | 1.26 | 0.00000698 | 1160 |
| Loss of Function | 4.05 | 2 | 22.9 | 0.0872 | 0.00000116 | 276 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000053 | 0.000044 | rare |
| South Asian | 0.00017 | 0.00016 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Forms a voltage-independent potassium channel activated by intracellular calcium. Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization. The channel is blocked by apamin.;
Recessive Scores
- pRec
- 0.122
Intolerance Scores
- RVIS EVS
- -0.85
- RVIS percentile EVS
- 11.06
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.662
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |