KCNB1

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

Basic information

Region (hg38): 20:49293393-49484297

Links

ENSG00000158445 ∙ NCBI:3745 ∙ OMIM:600397 ∙ HGNC:6231 ∙ Uniprot:Q14721 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental and epileptic encephalopathy, 26 (Definitive), mode of inheritance: AD
• developmental and epileptic encephalopathy, 26 (Strong), mode of inheritance: AD
• developmental and epileptic encephalopathy, 26 (Strong), mode of inheritance: AD
• undetermined early-onset epileptic encephalopathy (Supportive), mode of inheritance: AD
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epileptic encephalopathy, early infantile, 26	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	25164438

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KCNB1 gene.

• Developmental and epileptic encephalopathy, 26 (527 variants)
• not provided (178 variants)
• not specified (43 variants)
• Inborn genetic diseases (25 variants)
• Epileptic encephalopathy (19 variants)
• Intellectual disability (11 variants)
• KCNB1-related condition (8 variants)
• Early infantile epileptic encephalopathy with suppression bursts (3 variants)
• developmental encephalopathy with epilepsy (3 variants)
• Neurodevelopmental delay (2 variants)
• Seizure (2 variants)
• Neurodevelopmental abnormality (1 variants)
• See cases (1 variants)
• 6 conditions (1 variants)
• Rare genetic intellectual disability (1 variants)
• Marfanoid habitus and intellectual disability (1 variants)
• Myoclonic absence seizure (1 variants)
• KCNB1-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KCNB1 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	176	9	187
missense	25	45	177	56	37	340
nonsense	5	7	5	2		19
start loss						0
frameshift	6	2	15			23
inframe indel	1	1	6			8
splice donor/acceptor (+/-2bp)						0
splice region			1	4		5
non coding			2	13	1	16
Total	37	55	207	247	47

Variants in KCNB1

This is a list of pathogenic ClinVar variants found in the KCNB1 region.

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

Position	Type	Phenotype	Significance	ClinVar
20-49367844-G-A			Uncertain significance (Dec 29, 2021)
20-49372912-T-G			Likely benign (Sep 29, 2018)
20-49372966-C-T		not specified	Likely benign (Jul 14, 2016)
20-49372988-T-C		Developmental and epileptic encephalopathy, 26	Benign (Sep 06, 2022)
20-49372990-C-T		not specified • Developmental and epileptic encephalopathy, 26	Benign (Apr 01, 2024)
20-49372999-C-T		Developmental and epileptic encephalopathy, 26 • Inborn genetic diseases	Conflicting classifications of pathogenicity (Sep 01, 2023)
20-49373000-G-A		Developmental and epileptic encephalopathy, 26	Uncertain significance (Oct 31, 2023)
20-49373002-G-A			Uncertain significance (Jan 01, 2020)
20-49373004-G-A		Developmental and epileptic encephalopathy, 26	Likely benign (Apr 02, 2019)
20-49373007-T-C		Developmental and epileptic encephalopathy, 26	Likely benign (Aug 05, 2022)
20-49373014-G-T		Developmental and epileptic encephalopathy, 26	Uncertain significance (Jun 04, 2023)
20-49373020-C-G		Developmental and epileptic encephalopathy, 26	Likely benign (Feb 15, 2023)
20-49373020-C-T		Developmental and epileptic encephalopathy, 26	Uncertain significance (Jan 22, 2023)
20-49373022-C-T		Developmental and epileptic encephalopathy, 26	Likely benign (Oct 13, 2023)
20-49373023-C-A		Developmental and epileptic encephalopathy, 26	Uncertain significance (Jun 20, 2023)
20-49373029-A-G		Developmental and epileptic encephalopathy, 26	Benign (Jan 15, 2024)
20-49373031-C-T		Developmental and epileptic encephalopathy, 26	Likely benign (Nov 30, 2018)
20-49373035-C-T		Developmental and epileptic encephalopathy, 26	Benign (Nov 18, 2023)
20-49373036-G-A		Developmental and epileptic encephalopathy, 26 • Inborn genetic diseases	Likely benign (Sep 29, 2023)
20-49373039-C-T		Developmental and epileptic encephalopathy, 26	Benign (Aug 17, 2023)
20-49373040-G-A		Developmental and epileptic encephalopathy, 26	Likely benign (Dec 31, 2023)
20-49373044-G-A		Developmental and epileptic encephalopathy, 26 • not specified	Likely benign (May 25, 2023)
20-49373045-G-A		Developmental and epileptic encephalopathy, 26	Benign (Feb 02, 2022)
20-49373045-G-T		Developmental and epileptic encephalopathy, 26	Uncertain significance (Aug 18, 2023)
20-49373048-A-G		Developmental and epileptic encephalopathy, 26	Benign (Aug 17, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KCNB1	protein_coding	protein_coding	ENST00000371741	2	118771

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000229	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.27	241	513	0.470	0.0000315	5666
Missense in Polyphen		38	257.15	0.14778		2827
Synonymous	1.08	190	210	0.905	0.0000138	1707
Loss of Function	4.54	0	24.0	0.00	0.00000138	277

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
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, but also in the pancreas and cardiovascular system. Contributes to the regulation of the action potential (AP) repolarization, duration and frequency of repetitive AP firing in neurons, muscle cells and endocrine cells and plays a role in homeostatic attenuation of electrical excitability throughout the brain (PubMed:23161216). Plays also a role in the regulation of exocytosis independently of its electrical function (By similarity). 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. Homotetrameric channels mediate a delayed-rectifier voltage-dependent outward potassium current that display rapid activation and slow inactivation in response to membrane depolarization (PubMed:8081723, PubMed:1283219, PubMed:10484328, PubMed:12560340, PubMed:19074135, PubMed:19717558, PubMed:24901643). Can form functional homotetrameric and heterotetrameric channels that contain variable proportions of KCNB2; channel properties depend on the type of alpha subunits that are part of the channel (By similarity). Can also form functional heterotetrameric channels with other alpha subunits that are non-conducting when expressed alone, such as KCNF1, KCNG1, KCNG3, KCNG4, KCNH1, KCNH2, KCNS1, KCNS2, KCNS3 and KCNV1, creating a functionally diverse range of channel complexes (PubMed:10484328, PubMed:11852086, PubMed:12060745, PubMed:19074135, PubMed:19717558, PubMed:24901643). Heterotetrameric channel activity formed with KCNS3 show increased current amplitude with the threshold for action potential activation shifted towards more negative values in hypoxic-treated pulmonary artery smooth muscle cells (By similarity). Channel properties are also modulated by cytoplasmic ancillary beta subunits such as AMIGO1, KCNE1, KCNE2 and KCNE3, slowing activation and inactivation rate of the delayed rectifier potassium channels (By similarity). 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. Major contributor to the slowly inactivating delayed-rectifier voltage- gated potassium current in neurons of the central nervous system, sympathetic ganglion neurons, neuroendocrine cells, pancreatic beta cells, cardiomyocytes and smooth muscle cells. Mediates the major part of the somatodendritic delayed-rectifier potassium current in hippocampal and cortical pyramidal neurons and sympathetic superior cervical ganglion (CGC) neurons that acts to slow down periods of firing, especially during high frequency stimulation. Plays a role in the induction of long-term potentiation (LTP) of neuron excitability in the CA3 layer of the hippocampus (By similarity). Contributes to the regulation of glucose-induced action potential amplitude and duration in pancreatic beta cells, hence limiting calcium influx and insulin secretion (PubMed:23161216). Plays a role in the regulation of resting membrane potential and contraction in hypoxia-treated pulmonary artery smooth muscle cells. May contribute to the regulation of the duration of both the action potential of cardiomyocytes and the heart ventricular repolarization QT interval. Contributes to the pronounced pro-apoptotic potassium current surge during neuronal apoptotic cell death in response to oxidative injury. May confer neuroprotection in response to hypoxia/ischemic insults by suppressing pyramidal neurons hyperexcitability in hippocampal and cortical regions (By similarity). Promotes trafficking of KCNG3, KCNH1 and KCNH2 to the cell surface membrane, presumably by forming heterotetrameric channels with these subunits (PubMed:12060745). Plays a role in the calcium-dependent recruitment and release of fusion-competent vesicles from the soma of neurons, neuroendocrine and glucose- induced pancreatic beta cells by binding key components of the fusion machinery in a pore-independent manner (By similarity). {ECO:0000250|UniProtKB:P15387, ECO:0000250|UniProtKB:Q03717, ECO:0000269|PubMed:10484328, ECO:0000269|PubMed:11852086, ECO:0000269|PubMed:12060745, ECO:0000269|PubMed:12560340, ECO:0000269|PubMed:1283219, ECO:0000269|PubMed:19074135, ECO:0000269|PubMed:19717558, ECO:0000269|PubMed:23161216, ECO:0000269|PubMed:24901643, ECO:0000269|PubMed:8081723}.
• Disease: DISEASE: Epileptic encephalopathy, early infantile, 26 (EIEE26) [MIM:616056]: 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. EIEE26 patients manifest multiple types of seizures, delayed psychomotor development, poor or absent speech, hypotonia, hypsarrhythmia. {ECO:0000269|PubMed:25164438, ECO:0000269|PubMed:26477325, ECO:0000269|PubMed:26503721}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Calcium Regulation in the Cardiac Cell;Neuronal System;Voltage gated Potassium channels;Potassium Channels (Consensus)

Recessive Scores

• pRec: 0.141

Intolerance Scores

• loftool: 0.00937
• rvis_EVS: -0.05
• rvis_percentile_EVS: 50.34

Haploinsufficiency Scores

• pHI: 0.699
• hipred: Y
• hipred_score: 0.729
• ghis: 0.470

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.877

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kcnb1
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype; endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: kcnb1
• Affected structure: tectal ventricle
• Phenotype tag: abnormal
• Phenotype quality: decreased size

Gene ontology

• Biological process: action potential;vesicle docking involved in exocytosis;glutamate receptor signaling pathway;positive regulation of norepinephrine secretion;cellular response to nutrient levels;positive regulation of catecholamine secretion;regulation of ion transmembrane transport;glucose homeostasis;positive regulation of calcium ion-dependent exocytosis;negative regulation of insulin secretion;regulation of insulin secretion;protein homooligomerization;cellular response to glucose stimulus;potassium ion transmembrane transport;protein localization to plasma membrane;positive regulation of protein targeting to membrane;regulation of action potential;positive regulation of long-term synaptic depression;regulation of motor neuron apoptotic process
• Cellular component: plasma membrane;voltage-gated potassium channel complex;integral component of membrane;lateral plasma membrane;cell junction;axon;dendrite;dendrite membrane;neuronal cell body membrane;sarcolemma;perikaryon;postsynaptic membrane
• Molecular function: voltage-gated potassium channel activity;delayed rectifier potassium channel activity;protein binding;ion channel binding;protein heterodimerization activity