KCNJ10

protein-coding

potassium inwardly rectifying channel subfamily J member 10, the group of Potassium inwardly rectifying channel subfamily J

Gene summary

This gene encodes a member of the inward rectifier-type potassium channel family, characterized by having a greater tendency to allow potassium to flow into, rather than out of, a cell. The encoded protein may form a heterodimer with another potassium channel protein and may be responsible for the potassium buffering action of glial cells in the brain. Mutations in this gene have been associated with seizure susceptibility of common idiopathic generalized epilepsy syndromes. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002241.5

Inheritance

AR, AD, Digenic

ClinVar variants

P:45U:212B:113

Top phenotype

Deafness, autosomal recessive 4, with enlarged vestibular aqueduct; Pendred syndrome, digenic; Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SESAME syndrome)

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr1:159,998,651-160,070,483

External References & Databases

Ensembl (ENSG00000177807)

Transcript & Mutation Effects

hg38 • Region Span ~71.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

EAST syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013005

Submitter: PanelApp Australia

EAST syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013005

Submitter: G2P

paroxysmal dyskinesiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015427

Submitter: PanelApp Australia

EAST syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013005

Submitter: Labcorp Genetics (formerly Invitae)

EAST syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013005

Submitter: Ambry Genetics

EAST syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013005

Submitter: ClinGen

KCNJ10 was first reported in relation to autosomal recessive EAST (epilepsy, ataxia, sensorineural deafness and kidney salt-wasting tubulopathy) Syndrome in 2009 (Scholl et al. 2009, PMID: 19289823; and Bockenhauer et al., 2009, PMID: 19420365). At 11 least variants (missense and nonsense mutations) have been reported in humans. Evidence supporting this gene-disease relationship includes case level data, and experimental data (biochemical functional, expression level evidence, and a mouse model). In summary, the evidence for this gene is ample, and this gene disease relationship has been replicated for well over three years (since 2009), so the relationship is definitive.

Pendred syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010134

Submitter: Orphanet

enlarged vestibular aqueduct syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0023069

Submitter: ClinGen

The KCNJ10 gene has been associated with enlarged vestibular aqueducts, and digenic inheritance with SLC26A4, using the ClinGen Clinical Validity Framework as of 7/7/17. KCNJ10 was first associated with this disease in humans as early as 2009 (Yang et al.). A heterozygous missense variant has been reported in two probands, who also carry a heterozygous likely pathogenic/pathogenic variant in SLC26A4. No segregation information is available. This gene-disease association claim is supported by functional studies, which are not convincing enough to confirm a digenic inheritance (15320950, 17959752, 19426954). In summary, there is convincing evidence disputing the association between KCNJ10 and enlarged vestibular aqueducts, and digenic inheritance with SLC26A4. More evidence is needed to either support or refute the role KCNJ10 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 2/20/18.

EAST syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013005

Submitter: Orphanet

Clinical Genomic Database (CGD)

Manifestation: Audiologic/Otolaryngologic; Neurologic; Renal

Intervention: Audiologic/Otolaryngologic; Renal

Rationale: Individuals with Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalances display early-onset electrolyte abnormalities (eg, hypokalemia, metabolic alkalosis, and hypomagnesemia due to renal salt wasting), and treatment related to electrolyte imbalances may be beneficial; Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalances manifests with deafness, as well as electrolyte abnormalities; Digenic inheritance has been reported

Refs: 19420365; 19289823; 19289823; 19426954; 21849804

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNJ10 variants in ClinVar

21 Conditions Cataloged

EAST syndromeTotal: 320

not providedTotal: 106

Autosomal recessive nonsyndromic hearing loss 4Total: 77

Inborn genetic diseasesTotal: 70

not specifiedTotal: 37

Pendred syndromeTotal: 29

KCNJ10-related disorderTotal: 24

Intellectual disabilityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002241.5. 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				103 clinvar	1 clinvar	104
missense	7 clinvar	19 clinvar	203 clinvar	7 clinvar	2 clinvar	238
nonsense	4 clinvar	3 clinvar	2 clinvar			9
start loss			1 clinvar			1
frameshift	7 clinvar	4 clinvar	5 clinvar			16
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	18	27	212	110	3	370

Highest pathogenic variant AF is 0.000019216344

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002241.5	RefSeq	NP_002232.2	1	MANE Select
ENST00000644903.1	Ensembl	ENSP00000495557.1	1	MANE Select
ENST00000509700.2	Ensembl	ENSP00000491416.1	2	Standard
ENST00000637644.1	Ensembl	ENSP00000490282.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kcnj10b	Danio rerio	Structure: whole organism Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

kcnj10b

Danio rerio

Structure: whole organism

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gastric acid secretion - Homo sapiens (human)
Neuronal System
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits
Activation of GABAB receptors
GABA B receptor activation

Biological Process

potassium ion transport
visual perception
adult walking behavior
central nervous system myelination
regulation of ion transmembrane transport

Molecular Function

inward rectifier potassium channel activity
protein binding
ATP binding
ATP-activated inward rectifier potassium channel activity
G-protein activated inward rectifier potassium channel activity

Cellular Component

plasma membrane
integral component of plasma membrane
basolateral plasma membrane
presynapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368089
Coding exons: 1
Length: 32782
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125734
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.48	161	223	0.722	0.0000134	2458
Missense (PolyPhen)		56	101.63	0.55099		1212
Synonymous	-0.151	87	85.2	1.02	0.00000457	815
Loss of Function	2.09	3	10.2	0.294	6.23e-7	109

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be responsible for potassium buffering action of glial cells in the brain. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium and cesium (By similarity). In the kidney, together with KCNJ16, mediates basolateral K(+) recycling in distal tubules; this process is critical for Na(+) reabsorption at the tubules. {ECO:0000250, ECO:0000305|PubMed:24561201}.;

Recessive Scores

pRec: 0.375

Intolerance Scores

LoFtool: 0.0834
RVIS EVS: 0.15
RVIS percentile EVS: 64.51

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

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