KCND3

potassium voltage-gated channel subfamily D member 3, the group of Potassium voltage-gated channels

Basic information

Region (hg38): 1:111770661-111989668

Previous symbols: [ "SCA22", "SCA19" ]

Links

ENSG00000171385 ∙ NCBI:3752 ∙ OMIM:605411 ∙ HGNC:6239 ∙ Uniprot:Q9UK17 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Brugada syndrome 9 (Limited), mode of inheritance: AD
• spinocerebellar ataxia type 19/22 (Strong), mode of inheritance: AD
• spinocerebellar ataxia type 19/22 (Supportive), mode of inheritance: AD
• spinocerebellar ataxia type 19/22 (Strong), mode of inheritance: AD
• spinocerebellar ataxia type 19/22 (Strong), mode of inheritance: AD
• Brugada syndrome 1 (Disputed Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Brugada syndrome 9	AD	Cardiovascular	Individuals have been described as manifesting with arrhythmias and sudden cardiac death, and early diagnosis may allow management (such as with ICD placement)	Cardiovascular; Neurologic	21349352; 22457051; 23280837; 23280838

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KCND3 gene.

• Spinocerebellar ataxia type 19/22 (247 variants)
• Cardiovascular phenotype (225 variants)
• not provided (137 variants)
• not specified (42 variants)
• Spinocerebellar ataxia type 19/22;Brugada syndrome 9 (11 variants)
• Inborn genetic diseases (9 variants)
• Brugada syndrome 9 (8 variants)
• Brugada syndrome 9;Spinocerebellar ataxia type 19/22 (5 variants)
• Neurodevelopmental delay (2 variants)
• Brugada syndrome (1 variants)
• KCND3-Related Disorder (1 variants)
• Intellectual disability;Seizure (1 variants)
• Primary dilated cardiomyopathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KCND3 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			2	155	6	163
missense	7	12	177	3		199
nonsense			2			2
start loss						0
frameshift			1			1
inframe indel	1					1
splice donor/acceptor (+/-2bp)						0
splice region			6	8	1	15
non coding			2	36	19	57
Total	8	12	184	194	25

Variants in KCND3

This is a list of pathogenic ClinVar variants found in the KCND3 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-111775819-A-AC			Likely benign (Nov 02, 2018)
1-111775852-A-G			Likely benign (Jun 28, 2018)
1-111775862-A-G			Benign (Jun 23, 2018)
1-111776085-C-T		Spinocerebellar ataxia type 19/22 • Cardiovascular phenotype	Uncertain significance (Dec 22, 2023)
1-111776086-G-A		Cardiovascular phenotype • Spinocerebellar ataxia type 19/22	Benign/Likely benign (Jan 22, 2024)
1-111776095-G-T		Spinocerebellar ataxia type 19/22	Likely benign (Sep 01, 2022)
1-111776099-A-G		Spinocerebellar ataxia type 19/22 • Brugada syndrome 9;Spinocerebellar ataxia type 19/22	Uncertain significance (Jul 10, 2023)
1-111776102-T-C		Spinocerebellar ataxia type 19/22	Uncertain significance (Aug 10, 2022)
1-111776103-T-C		Cardiovascular phenotype	Uncertain significance (Dec 03, 2021)
1-111776108-G-T			Uncertain significance (Dec 05, 2022)
1-111776111-A-G		Spinocerebellar ataxia type 19/22	Uncertain significance (Feb 15, 2018)
1-111776121-T-A		Spinocerebellar ataxia type 19/22 • Cardiovascular phenotype	Uncertain significance (Oct 30, 2022)
1-111776125-C-T		Cardiovascular phenotype • Spinocerebellar ataxia type 19/22	Conflicting classifications of pathogenicity (Oct 12, 2023)
1-111776126-G-A		Cardiovascular phenotype • Spinocerebellar ataxia type 19/22	Conflicting classifications of pathogenicity (Oct 28, 2023)
1-111776128-G-T		Spinocerebellar ataxia type 19/22	Likely benign (Jul 07, 2023)
1-111776148-G-T		Cardiovascular phenotype	Uncertain significance (Mar 13, 2024)
1-111776150-G-A		Spinocerebellar ataxia type 19/22	Uncertain significance (Sep 15, 2021)
1-111776150-G-C		Cardiovascular phenotype	Uncertain significance (Oct 11, 2022)
1-111776155-C-T		Spinocerebellar ataxia type 19/22 • Cardiovascular phenotype	Benign (Sep 12, 2023)
1-111776156-C-T		Spinocerebellar ataxia type 19/22 • Cardiovascular phenotype • Spinocerebellar ataxia type 19/22;Brugada syndrome 9	Uncertain significance (Apr 23, 2023)
1-111776157-G-A		Cardiovascular phenotype	Uncertain significance (Dec 01, 2021)
1-111776160-T-A		Spinocerebellar ataxia type 19/22	Uncertain significance (Sep 06, 2021)
1-111776166-C-T		Spinocerebellar ataxia type 19/22 • Brugada syndrome 9;Spinocerebellar ataxia type 19/22 • Cardiovascular phenotype	Uncertain significance (Apr 17, 2023)
1-111776172-G-A		Spinocerebellar ataxia type 19/22 • Cardiovascular phenotype	Uncertain significance (Aug 16, 2022)
1-111776179-C-T		Cardiovascular phenotype • Spinocerebellar ataxia type 19/22	Likely benign (Jan 26, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KCND3	protein_coding	protein_coding	ENST00000315987	7	218494

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.990	0.0103	125740	0	6	125746	0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.85	209	435	0.480	0.0000322	4293
Missense in Polyphen		7	43.252	0.16184		360
Synonymous	0.550	182	192	0.949	0.0000156	1343
Loss of Function	4.01	2	22.6	0.0886	0.00000109	251

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000578	0.0000578
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000177	0.0000176
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Pore-forming (alpha) subunit of voltage-gated rapidly inactivating A-type potassium channels. May contribute to I(To) current in heart and I(Sa) current in neurons. Channel properties are modulated by interactions with other alpha subunits and with regulatory subunits. {ECO:0000269|PubMed:10200233, ECO:0000269|PubMed:9843794}.
• Disease: DISEASE: Spinocerebellar ataxia 19 (SCA19) [MIM:607346]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA19 is a relatively mild, cerebellar ataxic syndrome with cognitive impairment, pyramidal tract involvement, tremor and peripheral neuropathy, and mild atrophy of the cerebellar hemispheres and vermis. {ECO:0000269|PubMed:23280837, ECO:0000269|PubMed:23280838, ECO:0000269|PubMed:28895081}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Brugada syndrome 9 (BRGDA9) [MIM:616399]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. {ECO:0000269|PubMed:21349352, ECO:0000269|PubMed:22457051}. Note=The gene represented in this entry may be involved in disease pathogenesis.
• Pathway: Antiarrhythmic Pathway, Pharmacodynamics;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;Neuronal System;Phase 1 - inactivation of fast Na+ channels;Cardiac conduction;Muscle contraction;Voltage gated Potassium channels;Potassium Channels (Consensus)

Recessive Scores

• pRec: 0.194

Intolerance Scores

• loftool: 0.0288
• rvis_EVS: -0.8
• rvis_percentile_EVS: 12.24

Haploinsufficiency Scores

• pHI: 0.375
• hipred: Y
• hipred_score: 0.728
• ghis: 0.705

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.370

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kcnd3

Gene ontology

• Biological process: potassium ion transport;regulation of ion transmembrane transport;protein homooligomerization;potassium ion transmembrane transport;membrane repolarization;membrane repolarization during cardiac muscle cell action potential;regulation of heart rate by cardiac conduction;potassium ion export across plasma membrane;membrane repolarization during ventricular cardiac muscle cell action potential;ventricular cardiac muscle cell membrane repolarization
• Cellular component: plasma membrane;voltage-gated potassium channel complex;integral component of membrane;dendrite;sarcolemma;neuronal cell body;GABA-ergic synapse;integral component of postsynaptic specialization membrane
• Molecular function: voltage-gated potassium channel activity;A-type (transient outward) potassium channel activity;protein binding;ion channel binding;metal ion binding;voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization;voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization