KCNQ5

protein-coding

potassium voltage-gated channel subfamily Q member 5, the group of Potassium voltage-gated channels

Gene summary

This gene is a member of the KCNQ potassium channel gene family that is differentially expressed in subregions of the brain and in skeletal muscle. The protein encoded by this gene yields currents that activate slowly with depolarization and can form heteromeric channels with the protein encoded by the KCNQ3 gene. Currents expressed from this protein have voltage dependences and inhibitor sensitivities in common with M-currents. They are also inhibited by M1 muscarinic receptor activation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

MANE transcript

NM_019842.4

Inheritance

ClinVar variants

P:40U:377B:364

Top phenotype

Intellectual developmental disorder, autosomal dominant 46

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr6:72,621,792-73,198,853

External References & Databases

Ensembl (ENSG00000185760)

Transcript & Mutation Effects

hg38 • Region Span ~577.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal dominant 46STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030911

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal dominant 46LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030911

Submitter: G2P

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

intellectual developmental disorder, autosomal dominant 46STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030911

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 46AD

Manifestation: Neurologic

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: 28669405

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNQ5 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 799

Inborn genetic diseasesTotal: 104

not specifiedTotal: 80

Intellectual disability, autosomal dominant 46Total: 79

KCNQ5-related disorderTotal: 42

Intellectual disabilityTotal: 4

Prostate cancerTotal: 1

Autosomal dominant non-syndromic intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019842.4. 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			4 clinvar	229 clinvar	8 clinvar	241
missense	8 clinvar	14 clinvar	351 clinvar	71 clinvar	52 clinvar	496
nonsense	3 clinvar	4 clinvar	10 clinvar			17
start loss	1 clinvar		1 clinvar			2
frameshift	6 clinvar	4 clinvar	9 clinvar	4 clinvar		23
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	18	22	377	304	60	781

Highest pathogenic variant AF is 0.000003717403

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019842.4	RefSeq	NP_062816.2	14	MANE Select
ENST00000370398.6	Ensembl	ENSP00000359425.1	14	MANE Select
NM_001160130.2	RefSeq	NP_001153602.1	13	Standard
NM_001160132.2	RefSeq	NP_001153604.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cholinergic synapse - Homo sapiens (human)
Celecoxib Pathway, Pharmacodynamics
ion channels and their functional role in vascular endothelium
Neuronal System
Voltage gated Potassium channels

Biological Process

regulation of ion transmembrane transport
potassium ion transmembrane transport

Molecular Function

voltage-gated potassium channel activity
delayed rectifier potassium channel activity
protein binding
calmodulin binding

Cellular Component

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

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000342056
Coding exons: 15
Length: 577055
Individuals with no LoFs: 125708
Homozygous LoFs: 0
Heterozygous LoFs: 40
Defined: 125748
p: 0.000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.32	289	497	0.581	0.0000276	6134
Missense (PolyPhen)		45	173.74	0.259		2005
Synonymous	-1.80	219	188	1.17	0.0000109	1926
Loss of Function	5.29	8	47.2	0.169	0.00000294	513

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.0012	0.0012	notable
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Associates with KCNQ3 to form a potassium channel which contributes to M-type current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons. Therefore, it is important in the regulation of neuronal excitability. May contribute, with other potassium channels, to the molecular diversity of a heterogeneous population of M- channels, varying in kinetic and pharmacological properties, which underlie this physiologically important current. Insensitive to tetraethylammonium, but inhibited by barium, linopirdine and XE991. Activated by niflumic acid and the anticonvulsant retigabine. As the native M-channel, the potassium channel composed of KCNQ3 and KCNQ5 is also suppressed by activation of the muscarinic acetylcholine receptor CHRM1. {ECO:0000269|PubMed:10787416, ECO:0000269|PubMed:11159685, ECO:0000269|PubMed:28669405}.;
Disease: DISEASE: Mental retardation, autosomal dominant 46 (MRD46) [MIM:617601]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD46 patients manifest developmental delay and mild to moderate intellectual disability. {ECO:0000269|PubMed:28669405}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.118

Intolerance Scores

LoFtool: 0.0121
RVIS EVS: -0.73
RVIS percentile EVS: 14.08

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.760

Gene Damage Prediction

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