GeneBe

KCNJ16

protein-coding

potassium inwardly rectifying channel subfamily J member 16, the group of Potassium inwardly rectifying channel subfamily J

Gene summary

Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which tends to allow potassium to flow into rather than out of a cell, can form heterodimers with two other inward-rectifier type potassium channels. It may function in fluid and pH balance regulation. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2014]

MANE transcript

NM_170741.4

Inheritance

AR

ClinVar variants

P:12U:10B:5

Top phenotype

Hypokalemic tubulopathy and deafness

gnomAD constraint

pLI —, LoF o/e 1.12

Max pathogenic AF

—

Genomic locus

chr17:70,053,429-70,135,608

External References & Databases

Ensembl (ENSG00000153822)NCBI Gene (3773)OMIM (605722)HGNC:6262GenCCUniProt (Q9NPI9)AlphaFoldClinVar (KCNJ16)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~82.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypokalemic tubulopathy and deafnessSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859167

Submitter: Labcorp Genetics (formerly Invitae)

inherited renal tubular diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015962

Submitter: PanelApp Australia

hypokalemic tubulopathy and deafnessMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859167

Submitter: Ambry Genetics

hypokalemic alkalosis, familial, with specific renal tubulopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009423

Submitter: ClinGen

KCNJ16 was first reported in relation to autosomal recessive hypokalemic tubulopathy and deafness, in 2021 (Schlingmann et al., 2021; PMID: 33811157). 9 variants (missense and nonsense) that have been reported in at least 10 probands in 3 publications (PMIDs: 33811157, 33840812, 37466410) are included in this curation. There were two additional cases of genetic evidence referenced in the curation, but these were not scored due to high allele frequency/evidence for benign impact of the variants (PMIDs: 39414394, 39467953). The mechanism of pathogenicity appears to be loss-of-function. This gene-disease association is also supported by experimental evidence (ie. rat/mouse models, expression-level evidence, biochemical functional evidence, interaction evidence; PMIDs: 21633011, 21047793, 28931751). Expression-level data from GTEx and Humphrey's lab shows expression in the kidney, especially the distal convoluted tubule. Rat/mouse model evidence indicates that mutants have hypotension; excessive urination with hypokalemic metabolic acidosis; and abnormally high levels of potassium, calcium, and magnesium in urine. Biochemical functional evidence shows that the protein forms a heterodimer channel with KCNJ10 to allow potassium into the cell, which helps maintain electrolyte homeostasis. KCNJ10 is definitive for autosomal EAST Syndrome (Epilepsy, Ataxia, Sensorineural Deafness, and Renal Tubulopathy). This is relevant since EAST Syndrome includes salt-wasting renal tubulopathy. There was also an kidney organoid model found (PMID: 39183338), but this was not scored since it is not as informative as a in vivo model. This gene-disease pair was originally evaluated by the Tubulopathy GCEP on December 7, 2022. It was reevaluated on October 1, 2025 (SOP Version 11). As a result of this reevaluation, the classification increased from strong to definitive with the addition of genetic evidence (PMID: 37466410) that fulfilled the replication over time requirement.

Clinical Genomic Database (CGD)

Hypokalemic tubulopathy and deafnessAR

Manifestation: Audiologic/Otolaryngologic; Renal

Intervention: Audiologic/Otolaryngologic; Renal

Rationale: Early recognition of hearing impairment may improve outcomes, including related to speech and language development; The condition can involve sequelae of renal disease (eg, including renal salt wasting), and awareness may allow medical interventions related to kidney function

Refs: 33811157Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNJ16 variants in ClinVar

6 Conditions Cataloged
not providedTotal: 14
Hypokalemic tubulopathy and deafnessTotal: 14
KCNJ16-related disorderTotal: 3
Brugada syndrome 1Total: 1
not specifiedTotal: 1
First degree atrioventricular blockTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_170741.4. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
2
clinvar
 4
missense
4
clinvar
2
clinvar
8
clinvar
1
clinvar
 15
nonsense
2
clinvar
4
clinvar
2
clinvar
 8
start loss
0
frameshift
0
splice donor/acceptor (+/-2bp)
0
Total66102327

Highest pathogenic variant AF is 0.00056259276

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 67 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_170741.4RefSeqNP_733937.31MANE Select
ENST00000392671.6EnsemblENSP00000376439.11MANE Select
NM_001270422.2RefSeqNP_001257351.11Standard
NM_001291622.3RefSeqNP_001278551.21Standard

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
  • regulation of ion transmembrane transport
  • potassium ion import across plasma membrane

Molecular Function

  • inward rectifier potassium channel activity
  • G-protein activated inward rectifier potassium channel activity

Cellular Component

  • plasma membrane
  • voltage-gated potassium channel complex
  • basolateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000392670
Coding exons
1
Length
82180
Individuals with no LoFs
125562
Homozygous LoFs
0
Heterozygous LoFs
186
Defined
125748
p
0.000740
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.002202382381.000.00001332767
Missense (PolyPhen)116111.321.0421302
Synonymous-0.1178987.61.020.00000511810
Loss of Function-0.4141614.31.120.00000103152

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000980.00068rare
Latino/Admixed American0.00160.0016notable
Ashkenazi Jewish00.0absent
East Asian0.000600.00060rare
Finnish0.000370.00037rare
European (Non-Finnish)0.000700.00070rare
South Asian0.000690.00069rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: 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. KCNJ16 may be involved in the regulation of fluid and pH balance. In the kidney, together with KCNJ10, mediates basolateral K(+) recycling in distal tubules; this process is critical for Na(+) reabsorption at the tubules (PubMed:24561201). {ECO:0000305|PubMed:24561201}.;

Recessive Scores

pRec
0.149

Intolerance Scores

RVIS EVS
-0.91
RVIS percentile EVS
9.96

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
N
Indispensability score
0.381

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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