KCND2

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

Basic information

Region (hg38): 7:120273174-120750337

Links

ENSG00000184408 ∙ NCBI:3751 ∙ OMIM:605410 ∙ HGNC:6238 ∙ Uniprot:Q9NZV8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• complex neurodevelopmental disorder (Limited), mode of inheritance: AD

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KCND2 gene.

• Early myoclonic encephalopathy (290 variants)
• not provided (28 variants)
• Inborn genetic diseases (15 variants)
• not specified (4 variants)
• KCND2-associated neurodevelopmental syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KCND2 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			4	97	5	106
missense	4	3	135	10	1	153
nonsense			3			3
start loss						0
frameshift			5			5
inframe indel			3			3
splice donor/acceptor (+/-2bp)			3			3
splice region			9	7	2	18
non coding				15	11	26
Total	4	3	153	122	17

Variants in KCND2

This is a list of pathogenic ClinVar variants found in the KCND2 region.

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

Position	Type	Phenotype	Significance	ClinVar
7-120273428-C-T			Benign (May 13, 2021)
7-120273436-A-C			Benign (May 12, 2021)
7-120274636-G-T		Early myoclonic encephalopathy	Uncertain significance (Aug 04, 2022)
7-120274644-G-T		Early myoclonic encephalopathy	Uncertain significance (Dec 24, 2021)
7-120274645-G-A		Inborn genetic diseases • Early myoclonic encephalopathy	Uncertain significance (Mar 04, 2023)
7-120274646-T-G		Early myoclonic encephalopathy	Uncertain significance (Sep 25, 2023)
7-120274648-G-A		Early myoclonic encephalopathy	Uncertain significance (Dec 21, 2023)
7-120274649-C-A		Early myoclonic encephalopathy	Uncertain significance (Dec 05, 2021)
7-120274649-C-G		Early myoclonic encephalopathy	Uncertain significance (Aug 15, 2022)
7-120274651-G-A		Early myoclonic encephalopathy	Uncertain significance (Nov 27, 2023)
7-120274652-C-A		Early myoclonic encephalopathy	Uncertain significance (Jul 09, 2022)
7-120274653-G-C		Early myoclonic encephalopathy	Likely benign (Jan 15, 2024)
7-120274659-G-C		Early myoclonic encephalopathy	Likely benign (Jul 12, 2022)
7-120274659-G-T		Early myoclonic encephalopathy	Likely benign (Dec 12, 2023)
7-120274663-T-C		Early myoclonic encephalopathy	Likely benign (Oct 08, 2023)
7-120274665-T-G		Early myoclonic encephalopathy	Likely benign (Nov 08, 2023)
7-120274671-G-A		Early myoclonic encephalopathy	Likely benign (Nov 11, 2022)
7-120274674-A-G		Early myoclonic encephalopathy	Likely benign (Jun 19, 2021)
7-120274680-T-C		Early myoclonic encephalopathy	Likely benign (Jan 20, 2023)
7-120274683-C-T		Early myoclonic encephalopathy	Likely benign (Sep 25, 2023)
7-120274684-G-C			Uncertain significance (Mar 09, 2022)
7-120274693-C-G		Early myoclonic encephalopathy	Uncertain significance (May 16, 2022)
7-120274696-G-C		Early myoclonic encephalopathy • Inborn genetic diseases	Uncertain significance (Jul 06, 2023)
7-120274701-C-G		Early myoclonic encephalopathy	Likely benign (Jul 25, 2023)
7-120274701-C-T		Early myoclonic encephalopathy	Likely benign (Nov 03, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KCND2	protein_coding	protein_coding	ENST00000331113	6	476664

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0125	0.987	125733	0	15	125748	0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.51	189	382	0.494	0.0000244	4118
Missense in Polyphen		56	181.83	0.30799		1930
Synonymous	0.452	147	154	0.954	0.0000111	1281
Loss of Function	3.17	8	25.1	0.318	0.00000155	256

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000580	0.0000580
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.00	0.00
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000883	0.0000879
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. Mediates the major part of the dendritic A-type current I(SA) in brain neurons (By similarity). This current is activated at membrane potentials that are below the threshold for action potentials. It regulates neuronal excitability, prolongs the latency before the first spike in a series of action potentials, regulates the frequency of repetitive action potential firing, shortens the duration of action potentials and regulates the back-propagation of action potentials from the neuronal cell body to the dendrites. Contributes to the regulation of the circadian rhythm of action potential firing in suprachiasmatic nucleus neurons, which regulates the circadian rhythm of locomotor activity (By similarity). Functions downstream of the metabotropic glutamate receptor GRM5 and plays a role in neuronal excitability and in nociception mediated by activation of GRM5 (By similarity). Mediates the transient outward current I(to) in rodent heart left ventricle apex cells, but not in human heart, where this current is mediated by another family member. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient (PubMed:10551270, PubMed:15454437, PubMed:14695263, PubMed:14623880, PubMed:14980201, PubMed:16934482, PubMed:24811166, PubMed:24501278). The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:11507158). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCND2 and KCND3; channel properties depend on the type of pore-forming alpha subunits that are part of the channel. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes. Interaction with specific isoforms of the regulatory subunits KCNIP1, KCNIP2, KCNIP3 or KCNIP4 strongly increases expression at the cell surface and thereby increases channel activity; it modulates the kinetics of channel activation and inactivation, shifts the threshold for channel activation to more negative voltage values, shifts the threshold for inactivation to less negative voltages and accelerates recovery after inactivation (PubMed:15454437, PubMed:14623880, PubMed:14980201, PubMed:19171772, PubMed:24501278, PubMed:24811166). Likewise, interaction with DPP6 or DPP10 promotes expression at the cell membrane and regulates both channel characteristics and activity (By similarity). {ECO:0000250|UniProtKB:Q63881, ECO:0000250|UniProtKB:Q9Z0V2, ECO:0000269|PubMed:10551270, ECO:0000269|PubMed:10729221, ECO:0000269|PubMed:11507158, ECO:0000269|PubMed:14623880, ECO:0000269|PubMed:14695263, ECO:0000269|PubMed:14980201, ECO:0000269|PubMed:15454437, ECO:0000269|PubMed:16934482, ECO:0000269|PubMed:19171772, ECO:0000269|PubMed:24501278, ECO:0000269|PubMed:24811166}.
• Disease: DISEASE: Note=KNCD2 mutations have been found in a family with autism and epilepsy and may play a role in disease pathogenesis. Autism is a complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Epilepsy is characterized by paroxysmal transient disturbances of the electrical activity of the brain that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system. {ECO:0000269|PubMed:24501278}.; DISEASE: Note=A KCND2 mutation leading to the production of a C- terminally truncated protein has been identified in a patient with epilepsy. Epilepsy is characterized by paroxysmal transient disturbances of the electrical activity of the brain that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system. {ECO:0000269|PubMed:16934482}.
• Pathway: Serotonergic synapse - Homo sapiens (human);Levomethadyl Acetate Action Action Pathway;Fluoxetine Action Pathway;Citalopram Action Pathway;Escitalopram Action Pathway;Imipramine Action Pathway;Desipramine Action Pathway;Levallorphan Action Pathway;Dimethylthiambutene Action Pathway;Ethylmorphine Action Pathway;Pentazocine Action Pathway;Naltrexone Action Pathway;Buprenorphine Action Pathway;Alvimopan Action Pathway;Naloxone Action Pathway;Dihydromorphine Action Pathway;Nicotine Action Pathway;Nalbuphine Action Pathway;Ketobemidone Action Pathway;Lidocaine (Local Anaesthetic) Action Pathway;Mepivacaine Action Pathway;Chloroprocaine Action Pathway;Cocaine Action Pathway;Dibucaine Action Pathway;Levobupivacaine Action Pathway;Benzocaine Action Pathway;Bupivacaine Action Pathway;Levorphanol Action Pathway;Propoxyphene Action Pathway;Tramadol Action Action Pathway;Diphenoxylate Action Pathway;Anileridine Action Pathway;Methadone Action Pathway;Oxycodone Action Pathway;Oxybuprocaine Action Pathway;Prilocaine Action Pathway;Procaine Action Pathway;Proparacaine Action Pathway;Ropivacaine Action Pathway;Codeine Action Pathway;Morphine Action Pathway;Heroin Action Pathway;Alfentanil Action Pathway;Oxymorphone Action Pathway;Hydrocodone Action Pathway;Hydromorphone Action Pathway;Sufentanil Action Pathway;Remifentanil Action Pathway;Fentanyl Action Pathway;Carfentanil Action Pathway;3-Methylthiofentanyl Action Pathway;Methadyl Acetate Action Pathway;Dezocine 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: 0.152

Intolerance Scores

• loftool: 0.0711
• rvis_EVS: -0.65
• rvis_percentile_EVS: 16.44

Haploinsufficiency Scores

• pHI: 0.215
• hipred: Y
• hipred_score: 0.745
• ghis: 0.617

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.832

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kcnd2
• 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); 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: action potential;chemical synaptic transmission;neuronal action potential;sensory perception of pain;regulation of ion transmembrane transport;locomotor rhythm;protein homooligomerization;regulation of postsynaptic membrane potential;cellular response to hypoxia;potassium ion transmembrane transport
• Cellular component: plasma membrane;integral component of plasma membrane;voltage-gated potassium channel complex;postsynaptic density;integral component of membrane;cell junction;dendrite;intrinsic component of plasma membrane;neuronal cell body membrane;dendritic spine;perikaryon;plasma membrane raft;postsynaptic membrane;glutamatergic synapse;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;metal ion binding;voltage-gated ion channel activity involved in regulation of postsynaptic membrane potential