KCNA1

potassium voltage-gated channel subfamily A member 1, the group of Potassium voltage-gated channels

Basic information

Region (hg38): 12:4909904-4918256

Previous symbols: [ "AEMK" ]

Links

ENSG00000111262 ∙ NCBI:3736 ∙ OMIM:176260 ∙ HGNC:6218 ∙ Uniprot:Q09470 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• episodic ataxia type 1 (Strong), mode of inheritance: AD
• episodic ataxia type 1 (Definitive), mode of inheritance: AD
• developmental and epileptic encephalopathy (Supportive), mode of inheritance: AD
• episodic ataxia type 1 (Supportive), mode of inheritance: AD
• episodic kinesigenic dyskinesia 1 (Supportive), mode of inheritance: AD
• isolated autosomal dominant hypomagnesemia, Glaudemans type (Supportive), mode of inheritance: AD
• episodic ataxia type 1 (Strong), mode of inheritance: AD
• episodic ataxia type 1 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Episodic ataxia, type 1/myokymia syndrome	AD	Renal	Individuals can have severe hypomagnesemia, which is responsive to magnesium therapy	Neurologic; Renal	7842011; 11026449; 17136396; 19307729
For episodic ataxia medical treatment (eg, with phenytoin) may be effective, but the benefit of an early (genetic) diagnosis is unclear

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KCNA1 gene.

• Episodic ataxia type 1 (479 variants)
• not provided (100 variants)
• Hereditary episodic ataxia (70 variants)
• Myokymia (53 variants)
• Inborn genetic diseases (17 variants)
• not specified (14 variants)
• KCNA1-related condition (2 variants)
• Epileptic encephalopathy (1 variants)
• Generalized epilepsy-paroxysmal dyskinesia syndrome (1 variants)
• Episodic kinesigenic dyskinesia (1 variants)
• See cases (1 variants)
• KCNA1-related disorders (1 variants)
• Episodic ataxia/myokymia syndrome (1 variants)
• Myokymia 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KCNA1 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			9	127	5	141
missense	8	15	203	3		229
nonsense	2		8			10
start loss			3		1	4
frameshift			2			2
inframe indel		1	3			4
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			84	34	19	137
Total	10	16	312	164	25

Variants in KCNA1

This is a list of pathogenic ClinVar variants found in the KCNA1 region.

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

Position	Type	Phenotype	Significance	ClinVar
12-4909969-C-T		Episodic ataxia type 1	Benign/Likely benign (May 01, 2023)
12-4909972-G-T		Episodic ataxia type 1 • Myokymia	Uncertain significance (Jan 12, 2018)
12-4909978-C-T		Hereditary episodic ataxia • Episodic ataxia type 1	Uncertain significance (Jan 13, 2018)
12-4910044-C-T		Hereditary episodic ataxia • Episodic ataxia type 1	Uncertain significance (Jan 12, 2018)
12-4910053-C-T		Episodic ataxia type 1 • Myokymia	Benign (Jan 13, 2018)
12-4910103-A-G		Episodic ataxia type 1	Uncertain significance (Jan 15, 2018)
12-4910145-CGA-C		Hereditary episodic ataxia • Myokymia	Likely benign (Jun 14, 2016)
12-4910163-T-A		Episodic ataxia type 1	Uncertain significance (Jan 13, 2018)
12-4910173-C-T		Hereditary episodic ataxia • Episodic ataxia type 1	Benign (Jan 12, 2018)
12-4910281-C-G		Episodic ataxia type 1 • Hereditary episodic ataxia	Benign (Jan 13, 2018)
12-4910328-G-T		Episodic ataxia type 1 • Hereditary episodic ataxia	Uncertain significance (Jan 12, 2018)
12-4910374-C-T		Episodic ataxia type 1	Benign (Mar 14, 2018)
12-4910376-G-C		Episodic ataxia type 1 • Myokymia	Uncertain significance (Jan 13, 2018)
12-4910384-C-G		Episodic ataxia type 1	Uncertain significance (Jan 12, 2018)
12-4910849-A-G		Episodic ataxia type 1	Uncertain significance (Jan 12, 2018)
12-4910892-A-G		Episodic ataxia type 1 • Hereditary episodic ataxia	Uncertain significance (Jan 13, 2018)
12-4910895-A-AG		Myokymia • Hereditary episodic ataxia	Likely benign (Jun 14, 2016)
12-4910897-G-C		Episodic ataxia type 1 • Myokymia	Uncertain significance (Jan 12, 2018)
12-4910946-C-G		Episodic ataxia type 1	Uncertain significance (Jan 13, 2018)
12-4910951-C-T		Episodic ataxia type 1 • Hereditary episodic ataxia	Benign/Likely benign (Jan 13, 2018)
12-4910959-C-A		Episodic ataxia type 1	Uncertain significance (Jan 12, 2018)
12-4911077-AAAC-A		Myokymia • Hereditary episodic ataxia	Uncertain significance (Jun 14, 2016)
12-4911144-C-A		Myokymia • Episodic ataxia type 1	Benign/Likely benign (Jan 01, 2023)
12-4911149-C-G		Myokymia • Episodic ataxia type 1	Uncertain significance (Jan 13, 2018)
12-4911183-C-T		Episodic ataxia type 1	Uncertain significance (Jan 15, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KCNA1	protein_coding	protein_coding	ENST00000382545	1	21457

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0760	0.914	125741	0	7	125748	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.33	148	314	0.472	0.0000216	3296
Missense in Polyphen		37	167.35	0.22109		1777
Synonymous	-0.948	154	140	1.10	0.0000112	985
Loss of Function	2.23	4	12.5	0.319	6.35e-7	141

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000615	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000553	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000352	0.0000352
Middle Eastern	0.0000553	0.0000544
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 kidney (PubMed:19903818). Contributes to the regulation of the membrane potential and nerve signaling, and prevents neuronal hyperexcitability (PubMed:17156368). 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). 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:12077175, PubMed:17156368). 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 (PubMed:12077175, PubMed:17156368). 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 KCNA1 forms a delayed-rectifier potassium channel that opens in response to membrane depolarization, followed by slow spontaneous channel closure (PubMed:19912772, PubMed:19968958, PubMed:19307729, PubMed:19903818). In contrast, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation (PubMed:17156368). Regulates neuronal excitability in hippocampus, especially in mossy fibers and medial perforant path axons, preventing neuronal hyperexcitability. Response to toxins that are selective for KCNA1, respectively for KCNA2, suggests that heteromeric potassium channels composed of both KCNA1 and KCNA2 play a role in pacemaking and regulate the output of deep cerebellar nuclear neurons (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) release (By similarity). Plays a role in regulating the generation of action potentials and preventing hyperexcitability in myelinated axons of the vagus nerve, and thereby contributes to the regulation of heart contraction (By similarity). Required for normal neuromuscular responses (PubMed:11026449, PubMed:17136396). Regulates the frequency of neuronal action potential firing in response to mechanical stimuli, and plays a role in the perception of pain caused by mechanical stimuli, but does not play a role in the perception of pain due to heat stimuli (By similarity). Required for normal responses to auditory stimuli and precise location of sound sources, but not for sound perception (By similarity). The use of toxins that block specific channels suggest that it contributes to the regulation of the axonal release of the neurotransmitter dopamine (By similarity). Required for normal postnatal brain development and normal proliferation of neuronal precursor cells in the brain (By similarity). Plays a role in the reabsorption of Mg(2+) in the distal convoluted tubules in the kidney and in magnesium ion homeostasis, probably via its effect on the membrane potential (PubMed:23903368, PubMed:19307729). {ECO:0000250|UniProtKB:P10499, ECO:0000269|PubMed:11026449, ECO:0000269|PubMed:12077175, ECO:0000269|PubMed:15837928, ECO:0000269|PubMed:17136396, ECO:0000269|PubMed:17156368, ECO:0000269|PubMed:19307729, ECO:0000269|PubMed:19903818, ECO:0000269|PubMed:19912772, ECO:0000269|PubMed:19968958, ECO:0000269|PubMed:21106501, ECO:0000269|PubMed:23903368}.
• Disease: DISEASE: Episodic ataxia 1 (EA1) [MIM:160120]: An autosomal dominant disorder characterized by brief episodes of ataxia and dysarthria. Neurological examination during and between the attacks demonstrates spontaneous, repetitive discharges in the distal musculature (myokymia) that arise from peripheral nerve. Nystagmus is absent. {ECO:0000269|PubMed:10355668, ECO:0000269|PubMed:11013453, ECO:0000269|PubMed:11026449, ECO:0000269|PubMed:12077175, ECO:0000269|PubMed:15532032, ECO:0000269|PubMed:17156368, ECO:0000269|PubMed:7842011, ECO:0000269|PubMed:8541859, ECO:0000269|PubMed:8845167, ECO:0000269|PubMed:8871592, ECO:0000269|PubMed:9600245}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myokymia isolated 1 (MK1) [MIM:160120]: A condition characterized by spontaneous involuntary contraction of muscle fiber groups that can be observed as vermiform movement of the overlying skin. Electromyography typically shows continuous motor unit activity with spontaneous oligo- and multiplet-discharges of high intraburst frequency (myokymic discharges). Isolated spontaneous muscle twitches occur in many persons and have no grave significance. {ECO:0000269|PubMed:11026449, ECO:0000269|PubMed:17136396, ECO:0000269|PubMed:19307729, ECO:0000269|PubMed:19903818}. 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: 0.299

Intolerance Scores

• loftool: 0.0791
• rvis_EVS: -0.56
• rvis_percentile_EVS: 19.54

Haploinsufficiency Scores

• pHI: 0.688
• hipred: Y
• hipred_score: 0.651
• ghis: 0.610

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.803

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kcna1
• Phenotype: muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); 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); hearing/vestibular/ear phenotype; vision/eye phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms 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)

Gene ontology

• Biological process: startle response;potassium ion transport;regulation of muscle contraction;chemical synaptic transmission;neuroblast proliferation;cell communication by electrical coupling;magnesium ion homeostasis;neuronal action potential;hippocampus development;neuronal signal transduction;cellular protein localization;regulation of membrane potential;neuromuscular process;detection of mechanical stimulus involved in sensory perception of pain;detection of mechanical stimulus involved in sensory perception of touch;protein homooligomerization;regulation of postsynaptic membrane potential;cellular response to magnesium ion;potassium ion transmembrane transport;regulation of presynaptic membrane potential;positive regulation of voltage-gated potassium channel activity
• Cellular component: endoplasmic reticulum;cytosol;plasma membrane;integral component of plasma membrane;voltage-gated potassium channel complex;cell surface;integral component of membrane;apical plasma membrane;cell junction;axon;dendrite;cytoplasmic vesicle;paranode region of axon;presynaptic membrane;neuronal cell body;perikaryon;axon terminus;juxtaparanode region of axon;calyx of Held;synapse;glutamatergic synapse;integral component of postsynaptic membrane;integral component of presynaptic membrane
• Molecular function: voltage-gated potassium channel activity;delayed rectifier potassium channel activity;potassium channel activity;protein binding;potassium ion transmembrane transporter activity;disordered domain specific binding;voltage-gated ion channel activity involved in regulation of presynaptic membrane potential;voltage-gated ion channel activity involved in regulation of postsynaptic membrane potential