KCNA2

potassium voltage-gated channel subfamily A member 2, the group of Potassium voltage-gated channels

Basic information

Region (hg38): 1:110519836-110631474

Links

ENSG00000177301 ∙ NCBI:3737 ∙ OMIM:176262 ∙ HGNC:6220 ∙ Uniprot:P16389 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• undetermined early-onset epileptic encephalopathy (Supportive), mode of inheritance: AD
• developmental and epileptic encephalopathy, 32 (Strong), mode of inheritance: AD
• undetermined early-onset epileptic encephalopathy (Strong), mode of inheritance: AD
• developmental and epileptic encephalopathy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 32	AD	General	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	Neurologic	25477152; 25751627
As with other forms of epilepsy, optimal seizure control is advantageous, and genetic diagnosis may aid with medication selection

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KCNA2 gene.

• Developmental and epileptic encephalopathy, 32 (308 variants)
• not provided (123 variants)
• Inborn genetic diseases (42 variants)
• not specified (3 variants)
• Neurodevelopmental disorder (2 variants)
• KCNA2-related condition (2 variants)
• Global developmental delay (1 variants)
• Intellectual disability;Seizure (1 variants)
• KCN2A-Related Disorder (1 variants)
• Autism spectrum disorder (1 variants)
• See cases (1 variants)
• Seizure (1 variants)
• Developmental and epileptic encephalopathy, 1 (1 variants)
• KCNA2-Related Disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KCNA2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				99	5	104
missense	11	24	177	12	1	225
nonsense	2	1	5			8
start loss						0
frameshift	2	3	13			18
inframe indel	1		2			3
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				13	20	33
Total	16	28	197	124	26

Variants in KCNA2

This is a list of pathogenic ClinVar variants found in the KCNA2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-110593843-G-C			Benign (Feb 06, 2021)
1-110593922-C-T		Developmental and epileptic encephalopathy, 32	Uncertain significance (Jun 29, 2021)
1-110593985-C-T			Benign (Jul 26, 2018)
1-110593989-G-A			Benign (Jul 15, 2018)
1-110601777-A-AAT			Benign (Aug 10, 2019)
1-110601788-A-G			Likely benign (Jul 31, 2018)
1-110601790-A-G			Benign (Jul 15, 2018)
1-110601792-A-G			Benign (Aug 10, 2019)
1-110601792-ATATG-A			Likely benign (Aug 06, 2019)
1-110601792-ATATGTG-A			Likely benign (Aug 26, 2019)
1-110601792-A-ATG			Likely benign (Jan 22, 2020)
1-110601794-A-G			Benign (Aug 10, 2019)
1-110601794-ATG-A			Benign (Aug 10, 2019)
1-110601794-ATGTG-A			Benign (Aug 10, 2019)
1-110601794-A-ATG			Benign (Aug 10, 2019)
1-110601794-A-ATGTG			Likely benign (Aug 24, 2019)
1-110601798-G-A			Benign (Aug 22, 2019)
1-110601828-G-A			Benign (Aug 10, 2019)
1-110601828-G-GTA			Likely benign (Aug 06, 2019)
1-110601828-G-GTGTGTA			Likely benign (Aug 10, 2019)
1-110601828-G-GTGTGTGTA			Benign (Aug 10, 2019)
1-110601828-G-GTGTGTGTGTA			Likely benign (Aug 21, 2019)
1-110601828-G-GTGTGTGTGTGTA			Likely benign (Aug 06, 2019)
1-110601904-T-G			Benign (Jul 15, 2018)
1-110602038-C-T			Likely benign (Jan 03, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KCNA2	protein_coding	protein_coding	ENST00000485317	1	37895

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.911	0.0893	125743	0	5	125748	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.83	99	279	0.355	0.0000152	3300
Missense in Polyphen		35	151.91	0.23041		1835
Synonymous	-0.0350	109	109	1.00	0.00000579	988
Loss of Function	3.32	2	16.6	0.121	0.00000115	176

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000152	0.000152
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000879	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the cardiovascular system. Prevents aberrant action potential firing and regulates neuronal output. Forms tetrameric potassium- selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:19912772, PubMed:8495559, PubMed:11211111, PubMed:23769686). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNA7, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:8495559, PubMed:20220134). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation of delayed rectifier potassium channels. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Homotetrameric KCNA2 forms a delayed-rectifier potassium channel that opens in response to membrane depolarization, followed by slow spontaneous channel closure (PubMed:19912772, PubMed:23769686). In contrast, a heteromultimer formed by KCNA2 and KCNA4 shows rapid inactivation (PubMed:8495559). Regulates neuronal excitability and plays a role as pacemaker in the regulation of neuronal action potentials (By similarity). KCNA2- containing channels play a presynaptic role and prevent hyperexcitability and aberrant action potential firing (By similarity). Response to toxins that are selective for KCNA2- containing potassium channels suggests that in Purkinje cells, dendritic subthreshold KCNA2-containing potassium channels prevent random spontaneous calcium spikes, suppressing dendritic hyperexcitability without hindering the generation of somatic action potentials, and thereby play an important role in motor coordination (By similarity). Plays a role in the induction of long-term potentiation of neuron excitability in the CA3 layer of the hippocampus (By similarity). May function as down-stream effector for G protein-coupled receptors and inhibit GABAergic inputs to basolateral amygdala neurons (By similarity). May contribute to the regulation of neurotransmitter release, such as gamma-aminobutyric acid (GABA) (By similarity). Contributes to the regulation of the axonal release of the neurotransmitter dopamine (By similarity). Reduced KCNA2 expression plays a role in the perception of neuropathic pain after peripheral nerve injury, but not acute pain (By similarity). Plays a role in the regulation of the time spent in non-rapid eye movement (NREM) sleep (By similarity). {ECO:0000250|UniProtKB:P63141, ECO:0000250|UniProtKB:P63142, ECO:0000269|PubMed:11211111, ECO:0000269|PubMed:19912772, ECO:0000269|PubMed:20220134, ECO:0000269|PubMed:23769686, ECO:0000269|PubMed:8495559, ECO:0000305}.
• Disease: DISEASE: Epileptic encephalopathy, early infantile, 32 (EIEE32) [MIM:616366]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. {ECO:0000269|PubMed:25477152, ECO:0000269|PubMed:25751627}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Neuronal System;Voltage gated Potassium channels;Potassium Channels (Consensus)

Recessive Scores

• pRec: 0.215

Intolerance Scores

• loftool: 0.0272
• rvis_EVS: -0.43
• rvis_percentile_EVS: 25.15

Haploinsufficiency Scores

• pHI: 0.433
• hipred: Y
• hipred_score: 0.851
• ghis: 0.645

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.844

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Low	Low
Primary Immunodeficiency	Medium	Low	Medium
Cancer	Medium	Low	Medium

Mouse Genome Informatics

• Gene name: Kcna2
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); growth/size/body region phenotype

Zebrafish Information Network

• Gene name: kcna2a
• Affected structure: locomotion
• Phenotype tag: abnormal
• Phenotype quality: process quality

Gene ontology

• Biological process: potassium ion transport;regulation of dopamine secretion;neuronal action potential;sensory perception of pain;optic nerve structural organization;regulation of ion transmembrane transport;regulation of circadian sleep/wake cycle, non-REM sleep;protein homooligomerization;potassium ion transmembrane transport
• Cellular component: endoplasmic reticulum membrane;plasma membrane;integral component of plasma membrane;voltage-gated potassium channel complex;integral component of membrane;lamellipodium;axon;dendrite;lamellipodium membrane;neuronal cell body membrane;paranodal junction;perikaryon;axon terminus;juxtaparanode region of axon;calyx of Held;integral component of presynaptic membrane
• Molecular function: voltage-gated potassium channel activity;delayed rectifier potassium channel activity;potassium channel activity;protein binding;outward rectifier potassium channel activity;kinesin binding