KCNV2

protein-coding

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

Gene summary

Voltage-gated potassium (Kv) 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. This gene encodes a member of the potassium voltage-gated channel subfamily V. This member is identified as a 'silent subunit', and it does not form homomultimers, but forms heteromultimers with several other subfamily members. Through obligatory heteromerization, it exerts a function-altering effect on other potassium channel subunits. This protein is strongly expressed in pancreas and has a weaker expression in several other tissues. [provided by RefSeq, Jul 2008]

MANE transcript

NM_133497.4

Inheritance

ClinVar variants

P:111U:477B:263

Top phenotype

Retinal cone dystrophy 3B

gnomAD constraint

pLI —, LoF o/e 1.88

Max pathogenic AF

—

Genomic locus

chr9:2,717,510-2,730,037

External References & Databases

Ensembl (ENSG00000168263)

Transcript & Mutation Effects

hg38 • Region Span ~12.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cone dystrophy with supernormal rod responseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012475

Submitter: PanelApp Australia

cone dystrophy with supernormal rod responseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012475

Submitter: Orphanet

cone dystrophy with supernormal rod responseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012475

Submitter: Labcorp Genetics (formerly Invitae)

cone dystrophy with supernormal rod responseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012475

Submitter: G2P

inherited retinal dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019118

Submitter: ClinGen

The *KCNV2* gene was first reported in relation to "cone dystrophy with supernormal rod responses" (CDSRR) with an autosomal recessive mode of inheritance in 2005 (PMID: 15722315, PMID:16909397). This disease is also referred to as retinal cone dystrophy 3B (MIM#: 610356). Probands have also been reported with similar diagnoses such as cone dystrophy or "achromatopsia and congenital cone dysfunction" (PMID: 18235024), so all of these cases have been lumped for the purposes of this gene curation under the more general disease term KCNV2-related retinopathy. This curation has scored genetic evidence from the first paper linking the phenotype with variants in the *KCNV2* gene by linkage analysis and Sanger sequencing in one family, followed by the analysis of a cohort of 10 additional probands (PMID:16909397). These probands have been included in the present curation, along with others from a cohort of 17 patients from 13 families ((PMID: 18235024). Numerous publications have collectively reported over 180 disease-causing variants, all of which are inferred to lead to loss-of-function. The variant types range from missense, in-frame indels, nonsense, and frameshift variants to large deletions and complex rearrangements. More cases were availbable in the literature, but the maximum score for genetic evidence had already been reached. The *KCNV2* encodes the regulatory subunit (Kv8.2) of voltage-gated potassium channels. These channels control the excitability of electrically active cells, and are made up of 4 subunits that create the central ion channel (PMID: 34063002). Disease-associated missense variants in yeast two-hybrid studies exhibit defective protein interaction with the *KCNB1* gene product Kv2.1 (PMID: 21882291), consistent with a loss-of-function mechanism of pathogenicity. Disease-associated missense variants also exhibit loss of interaction and altered electrophysiological function when exogenously expressed in HEK293 cells (PMID: 23115240). *Kcnv2* knockout mice exhibit a depressed a-wave and elevated b-wave, recapitulating the human abnormal response, accompanied by retinal changes including increased TUNEL-positive cells (PMID: 30820446). In summary, *KCNV2* is definitively associated with KCNV2-related retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a definitive classification. This classification has been approved by the ClinGen Retina GCEP on September 7th, 2023 (SOP Version 10).

Clinical Genomic Database (CGD)

Retinal cone dystrophy 3BAR

Manifestation: Ophthalmologic

Intervention: General

Rationale: 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

Refs: 16909397

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNV2 variants in ClinVar

17 Conditions Cataloged

not providedTotal: 740

Inborn genetic diseasesTotal: 156

KCNV2-related disorderTotal: 140

Cone dystrophy with supernormal rod responseTotal: 101

not specifiedTotal: 96

Retinal dystrophyTotal: 26

cone dystrophy with supernormal rod electroretinogramTotal: 8

Cone dystrophyTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_133497.4. 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			7 clinvar	215 clinvar	2 clinvar	224
missense	4 clinvar	28 clinvar	465 clinvar	43 clinvar	3 clinvar	543
nonsense	25 clinvar	21 clinvar	2 clinvar			48
start loss		1 clinvar				1
frameshift	17 clinvar	14 clinvar	3 clinvar			34
splice donor/acceptor (+/-2bp)		1 clinvar				1
Total	46	65	477	258	5	851

Highest pathogenic variant AF is 0.00025096885

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_133497.4	RefSeq	NP_598004.1	2	MANE Select
ENST00000382082.4	Ensembl	ENSP00000371514.3	2	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neuronal System
Voltage gated Potassium channels
Potassium Channels

Biological Process

regulation of ion transmembrane transport
protein homooligomerization
potassium ion transmembrane transport

Molecular Function

voltage-gated potassium channel activity

Cellular Component

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

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000382082
Coding exons: 2
Length: 12536
Individuals with no LoFs: 125633
Homozygous LoFs: 0
Heterozygous LoFs: 115
Defined: 125748
p: 0.000457

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-4.48	606	365	1.66	0.0000280	3503
Missense (PolyPhen)		216	133.17	1.622		1282
Synonymous	-5.24	253	167	1.52	0.0000145	1099
Loss of Function	-3.30	31	16.5	1.88	7.28e-7	175

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00056	0.00055	rare
Latino/Admixed American	0.00079	0.00078	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00050	0.00049	rare
Finnish	0.00020	0.00018	rare
European (Non-Finnish)	0.00046	0.00044	rare
South Asian	0.00040	0.00039	rare
Other	0.00068	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Potassium channel subunit. Modulates channel activity by shifting the threshold and the half-maximal activation to more negative values.;
Disease: DISEASE: Cone dystrophy retinal 3B (RCD3B) [MIM:610356]: A rare form of cone dystrophy associated with supernormal rod responses. The disorder is characterized by reduced visual acuity, photoaversion, night blindness, and abnormal color vision. At an early age, the retina shows subtle depigmentation at the macula and, later, more obvious areas of atrophy. {ECO:0000269|PubMed:16909397}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.122

Intolerance Scores

LoFtool: 0.0969
RVIS EVS: -0.84
RVIS percentile EVS: 11.45

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.630

Gene Damage Prediction

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