GeneBe

KCNN4

protein-coding

potassium calcium-activated channel subfamily N member 4, the group of Potassium calcium-activated channels

Gene summary

The protein encoded by this gene is part of a potentially heterotetrameric voltage-independent potassium channel that is activated by intracellular calcium. Activation is followed by membrane hyperpolarization, which promotes calcium influx. The encoded protein may be part of the predominant calcium-activated potassium channel in T-lymphocytes. This gene is similar to other KCNN family potassium channel genes, but it differs enough to possibly be considered as part of a new subfamily. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002250.3

Inheritance

AD, AR

ClinVar variants

P:4U:110B:38

Top phenotype

Dehydrated hereditary stomatocytosis 2

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr19:43,766,533-43,780,976

External References & Databases

Ensembl (ENSG00000104783)NCBI Gene (3783)OMIM (602754)HGNC:6293GenCCUniProt (O15554)AlphaFoldClinVar (KCNN4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~14.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

dehydrated hereditary stomatocytosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017910

Submitter: Orphanet

dehydrated hereditary stomatocytosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014737

Submitter: Labcorp Genetics (formerly Invitae)

dehydrated hereditary stomatocytosis 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014737

Submitter: Ambry Genetics

cystic fibrosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009061

Submitter: Orphanet

dehydrated hereditary stomatocytosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014737

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Dehydrated hereditary stomatocytosis 2AD

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals have been described with severe anemia, and interventions such as RBC transfusions, erythropoietin, and splenectomy may be indicated

Refs: 26148990; 26178367; 26198474Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNN4 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 72
Inborn genetic diseasesTotal: 57
Dehydrated hereditary stomatocytosis 2Total: 48
KCNN4-related disorderTotal: 24
not specifiedTotal: 22
Kartagener syndromeTotal: 1
Primary ciliary dyskinesia 5Total: 1
Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edemaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002250.3. 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
4
clinvar
26
clinvar
2
clinvar
 32
missense
2
clinvar
2
clinvar
98
clinvar
9
clinvar
 111
nonsense
2
clinvar
 2
start loss
0
frameshift
4
clinvar
 4
splice donor/acceptor (+/-2bp)
2
clinvar
1
clinvar
 3
Total22110362152
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002250.3RefSeqNP_002241.18MANE Select
ENST00000648319.1EnsemblENSP00000496939.18MANE Select
ENST00000598836.1EnsemblENSP00000471900.14Standard
ENST00000599720.5EnsemblENSP00000472513.12Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Protein digestion and absorption - Homo sapiens (human)
  • Salivary secretion - Homo sapiens (human)
  • Insulin secretion - Homo sapiens (human)
  • miR-targeted genes in leukocytes - TarBase
  • miR-targeted genes in lymphocytes - TarBase

Biological Process

  • immune system process
  • potassium ion transport
  • calcium ion transport
  • cell volume homeostasis
  • defense response

Molecular Function

  • potassium channel activity
  • protein binding
  • calmodulin binding
  • calcium-activated potassium channel activity
  • small conductance calcium-activated potassium channel activity

Cellular Component

  • plasma membrane
  • voltage-gated potassium channel complex
  • vesicle
  • neuron projection
  • neuronal cell body

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000262888
Coding exons
8
Length
14725
Individuals with no LoFs
125494
Homozygous LoFs
2
Heterozygous LoFs
251
Defined
125747
p
0.00101
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.621942690.7210.00001592695
Missense (PolyPhen)6399.9130.630551044
Synonymous0.7551081180.9120.00000688936
Loss of Function1.531320.50.6340.00000111202

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0100.010notable
Latino/Admixed American0.00130.0012notable
Ashkenazi Jewish0.000500.00050rare
East Asian0.000130.00011rare
Finnish0.000230.00023rare
European (Non-Finnish)0.000240.00023rare
South Asian0.000160.00016rare
Other0.000660.00065rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Forms a voltage-independent potassium channel that is activated by intracellular calcium (PubMed:26148990). Activation is followed by membrane hyperpolarization which promotes calcium influx. Required for maximal calcium influx and proliferation during the reactivation of naive T-cells. The channel is blocked by clotrimazole and charybdotoxin but is insensitive to apamin (PubMed:17157250, PubMed:18796614). {ECO:0000269|PubMed:17157250, ECO:0000269|PubMed:18796614, ECO:0000269|PubMed:26148990}.;
Disease
DISEASE: Dehydrated hereditary stomatocytosis 2 (DHS2) [MIM:616689]: An autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. Erythrocytes exhibit decreased total cation and potassium content that are not accompanied by a proportional net gain of sodium and water. Affected individuals typically manifest mild to moderate compensated hemolytic anemia, with an increased erythrocyte mean corpuscular hemoglobin concentration and a decreased osmotic fragility, both of which reflect cellular dehydration. Their red cells exhibit a panel of various shape abnormalities such as elliptocytes, hemighosts, schizocytes, and very rare stomatocytic cells. Complications such as splenomegaly and cholelithiasis, resulting from increased red cell trapping in the spleen and elevated bilirubin levels, respectively, may occur. {ECO:0000269|PubMed:26148990, ECO:0000269|PubMed:26178367, ECO:0000269|PubMed:26198474}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool
0.152
RVIS EVS
-0.12
RVIS percentile EVS
45.13

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.600

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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