KCNC2

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

Basic information

Region (hg38): 12:75040077-75209839

Links

ENSG00000166006 ∙ NCBI:3747 ∙ OMIM:176256 ∙ HGNC:6234 ∙ Uniprot:Q96PR1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental and epileptic encephalopathy 103 (Strong), mode of inheritance: AD
• developmental and epileptic encephalopathy 103 (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 103	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	31972370; 32392612; 34448338; 35314505

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KCNC2 gene.

• Developmental and epileptic encephalopathy 103 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KCNC2 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	1	3
missense	1	4	37	1	1	44
nonsense						0
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	1	4	38	3	2

Variants in KCNC2

This is a list of pathogenic ClinVar variants found in the KCNC2 region.

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

Position	Type	Phenotype	Significance	ClinVar
12-75042341-G-A		Inborn genetic diseases	Uncertain significance (Jun 13, 2023)
12-75042374-T-A		Inborn genetic diseases	Uncertain significance (Jan 07, 2022)
12-75043099-T-C		KCNC2-related disorder	Likely benign (Mar 28, 2024)
12-75043117-TG-T			Uncertain significance (Dec 01, 2022)
12-75048164-C-G		Inborn genetic diseases	Uncertain significance (Sep 13, 2023)
12-75048186-A-C		Inborn genetic diseases	Uncertain significance (Jun 03, 2024)
12-75048248-C-A		Inborn genetic diseases	Uncertain significance (Feb 07, 2023)
12-75048258-G-A			Uncertain significance (Jun 11, 2024)
12-75048298-A-C		Inborn genetic diseases	Uncertain significance (Apr 27, 2022)
12-75048298-A-T		Inborn genetic diseases	Uncertain significance (Jan 04, 2022)
12-75050407-A-T		Inborn genetic diseases	Uncertain significance (May 15, 2023)
12-75050413-C-T		Inborn genetic diseases	Uncertain significance (May 16, 2022)
12-75050425-C-A		Inborn genetic diseases	Uncertain significance (Sep 20, 2023)
12-75050432-A-C			Uncertain significance (Oct 23, 2023)
12-75050438-C-G		Inborn genetic diseases	Uncertain significance (Dec 06, 2022)
12-75050459-C-A		Inborn genetic diseases	Uncertain significance (May 23, 2024)
12-75050479-C-A		Inborn genetic diseases • KCNC2-related disorder	Uncertain significance (Jul 25, 2023)
12-75050581-T-G			Uncertain significance (May 11, 2023)
12-75050587-A-G			Likely pathogenic (Apr 03, 2023)
12-75050587-A-T		Neurodevelopmental delay	Likely pathogenic (-)
12-75050594-C-G		Developmental and epileptic encephalopathy 103	Pathogenic (Jun 15, 2022)
12-75050597-G-A		Developmental and epileptic encephalopathy 103	Conflicting classifications of pathogenicity (Nov 29, 2022)
12-75050597-G-T		Developmental and epileptic encephalopathy 103	Uncertain significance (Nov 12, 2022)
12-75050600-C-A		KCNC2-related disorder	Uncertain significance (Apr 07, 2021)
12-75050602-G-A		not specified	Uncertain significance (Sep 27, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KCNC2	protein_coding	protein_coding	ENST00000549446	4	169792

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.189	0.810	125738	0	10	125748	0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.98	204	364	0.561	0.0000186	4095
Missense in Polyphen		36	156.63	0.22984		1837
Synonymous	-2.01	189	157	1.20	0.00000880	1354
Loss of Function	3.07	5	19.7	0.254	0.00000105	240

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000309	0.0000309
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000530	0.0000527
Middle Eastern	0.00	0.00
South Asian	0.0000980	0.0000980
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. Contributes to the regulation of the fast action potential repolarization and in sustained high-frequency firing in neurons of the central nervous system. Homotetramer channels mediate delayed-rectifier voltage-dependent potassium currents that activate rapidly at high-threshold voltages and inactivate slowly. Forms tetrameric 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:15709110). Can form functional homotetrameric and heterotetrameric channels that contain variable proportions of KCNC1, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel. Channel properties may be modulated either by the association with ancillary subunits, such as KCNE1, KCNE2 or KCNE3 or indirectly by nitric oxide (NO) through a cGMP- and PKG- mediated signaling cascade, slowing channel activation and deactivation of delayed rectifier potassium channels (By similarity). Contributes to fire sustained trains of very brief action potentials at high frequency in retinal ganglion cells, thalamocortical and suprachiasmatic nucleus (SCN) neurons and in hippocampal and neocortical interneurons (PubMed:15709110). Sustained maximal action potential firing frequency in inhibitory hippocampal interneurons is negatively modulated by histamine H2 receptor activation in a cAMP- and protein kinase (PKA) phosphorylation-dependent manner. Plays a role in maintaining the fidelity of synaptic transmission in neocortical GABAergic interneurons by generating action potential (AP) repolarization at nerve terminals, thus reducing spike-evoked calcium influx and GABA neurotransmitter release. Required for long-range synchronization of gamma oscillations over distance in the neocortex. Contributes to the modulation of the circadian rhythm of spontaneous action potential firing in suprachiasmatic nucleus (SCN) neurons in a light-dependent manner (By similarity). {ECO:0000250|UniProtKB:P22462, ECO:0000250|UniProtKB:Q14B80, ECO:0000269|PubMed:15709110, ECO:0000305|PubMed:10414303, ECO:0000305|PubMed:11506885}.
• Disease: DISEASE: Note=A chromosomal aberration involving KCNC2 has been found in a mother and her two children with varying degrees of neurodevelopmental delay and cerebellar ataxia. One child also exhibits episodes of unresponsiveness suggestive of absence seizures and facial dysmorphism. Deletion at 12q21.1 deletes exons 3-5 of KCNC2. {ECO:0000269|PubMed:23475819}.
• Pathway: Neuronal System;Voltage gated Potassium channels;Potassium Channels (Consensus)

Recessive Scores

• pRec: 0.0978

Intolerance Scores

• loftool: 0.0257
• rvis_EVS: -0.82
• rvis_percentile_EVS: 11.68

Haploinsufficiency Scores

• pHI: 0.285
• hipred: Y
• hipred_score: 0.586
• ghis: 0.641

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.920

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kcnc2
• Phenotype: limbs/digits/tail 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); skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); muscle phenotype

Gene ontology

• Biological process: response to light intensity;response to organic cyclic compound;response to amine;globus pallidus development;response to magnesium ion;nitric oxide-cGMP-mediated signaling pathway;response to ethanol;regulation of insulin secretion;protein homooligomerization;protein heterooligomerization;cellular response to ammonium ion;cellular response to nitric oxide;potassium ion transmembrane transport;cellular response to toxic substance;regulation of presynaptic membrane potential;positive regulation of voltage-gated potassium channel activity;response to nerve growth factor
• Cellular component: plasma membrane;integral component of plasma membrane;voltage-gated potassium channel complex;membrane;integral component of membrane;basolateral plasma membrane;apical plasma membrane;cell junction;axon;dendrite;axolemma;vesicle;dendrite membrane;neuronal cell body membrane;presynaptic membrane;neuronal cell body;terminal bouton;perikaryon;synapse;postsynaptic membrane
• Molecular function: voltage-gated potassium channel activity;delayed rectifier potassium channel activity;ion channel binding;voltage-gated ion channel activity involved in regulation of presynaptic membrane potential