KCNA6

protein-coding

potassium voltage-gated channel subfamily A member 6, the group of Potassium voltage-gated channels|Protein phosphatase 1 regulatory subunits

Gene summary

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. It belongs to the delayed rectifier class. The coding region of this gene is intronless, and the gene is clustered with genes KCNA1 and KCNA5 on chromosome 12. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002235.5

Inheritance

ClinVar variants

P:4U:80B:6

Top phenotype

Inborn genetic diseases

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr12:4,809,334-4,813,318

External References & Databases

Ensembl (ENSG00000151079)

Transcript & Mutation Effects

hg38 • Region Span ~4.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNA6 variants in ClinVar

18 Conditions Cataloged

Inborn genetic diseasesTotal: 50

not providedTotal: 35

KCNA6-related conditionTotal: 4

Pes planusTotal: 1

Moderate global developmental delayTotal: 1

Pyloric stenosisTotal: 1

KCNA6-associated epileptic encephalopathyTotal: 1

EpicanthusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002235.5. 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			1 clinvar	3 clinvar	1 clinvar	5
missense	1 clinvar	3 clinvar	77 clinvar	2 clinvar		83
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	1	3	80	5	1	90

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002235.5	RefSeq	NP_002226.1	1	MANE Select
ENST00000280684.4	Ensembl	ENSP00000280684.3	1	MANE Select
XM_017019270.2	RefSeq	XP_016874759.1	1	Standard
XM_017019271.2	RefSeq	XP_016874760.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
mucin core 1 and core 2 <i>O</i>-glycosylation
Neuronal System
O-Glycan biosynthesis

Biological Process

potassium ion transport
regulation of ion transmembrane transport
protein homooligomerization
potassium ion transmembrane transport

Molecular Function

voltage-gated potassium channel activity
delayed rectifier potassium channel activity

Cellular Component

plasma membrane
integral component of plasma membrane
voltage-gated potassium channel complex
integral component of membrane
potassium channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000433855
Coding exons: 1
Length: 41936
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125748
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.05	180	338	0.533	0.0000206	3423
Missense (PolyPhen)		63	178.18	0.35358		1818
Synonymous	0.322	147	152	0.967	0.00000978	1151
Loss of Function	2.84	3	14.8	0.203	8.55e-7	135

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000045	0.000044	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient (PubMed:2347305, PubMed:14575698). The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:2347305, PubMed:14575698). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA6, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (By similarity). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (By similarity). Homotetrameric channels display rapid activation and slow inactivation (PubMed:2347305). {ECO:0000250|UniProtKB:P17659, ECO:0000269|PubMed:14575698, ECO:0000269|PubMed:2347305}.;

Recessive Scores

pRec: 0.121

Intolerance Scores

LoFtool: 0.0657
RVIS EVS: -0.52
RVIS percentile EVS: 21.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.136

Gene Damage Prediction

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