KCNN4

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

Basic information

Region (hg38): 19:43766533-43780976

Links

ENSG00000104783 ∙ NCBI:3783 ∙ OMIM:602754 ∙ HGNC:6293 ∙ Uniprot:O15554 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• dehydrated hereditary stomatocytosis 2 (Moderate), mode of inheritance: AD
• dehydrated hereditary stomatocytosis 2 (Strong), mode of inheritance: AD
• dehydrated hereditary stomatocytosis (Supportive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Dehydrated hereditary stomatocytosis 2	AD	Hematologic	Individuals have been described with severe anemia, and interventions such as RBC transfusions, erythropoietin, and splenectomy may be indicated	Hematologic	26148990; 26178367; 26198474

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KCNN4 gene.

• Dehydrated hereditary stomatocytosis 2 (1 variants)
• not provided (1 variants)
• Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KCNN4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				9	4	13
missense	2	2	39	3	1	47
nonsense						0
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)				1		1
splice region			2	1	1	4
non coding				2	18	20
Total	2	2	40	15	23

Variants in KCNN4

This is a list of pathogenic ClinVar variants found in the KCNN4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-43767555-C-A		Dehydrated hereditary stomatocytosis 2	Uncertain significance (Jul 08, 2021)
19-43767572-G-A		Inborn genetic diseases	Uncertain significance (Apr 06, 2024)
19-43767581-G-A		Inborn genetic diseases	Uncertain significance (Dec 03, 2021)
19-43767634-G-A		Dehydrated hereditary stomatocytosis 2 • KCNN4-related disorder	Uncertain significance (Sep 10, 2021)
19-43767658-C-T		Inborn genetic diseases	Conflicting classifications of pathogenicity (Aug 23, 2024)
19-43767668-T-G		KCNN4-related disorder	Uncertain significance (Jan 10, 2024)
19-43767694-A-G		KCNN4-related disorder	Uncertain significance (Sep 17, 2024)
19-43767723-G-A			Likely benign (Mar 18, 2022)
19-43767783-A-G			Benign (Jun 20, 2021)
19-43769027-C-T		Dehydrated hereditary stomatocytosis 2	Pathogenic (Nov 01, 2024)
19-43769364-T-C			Benign (Nov 12, 2018)
19-43769452-C-T		KCNN4-related disorder	Uncertain significance (Dec 20, 2023)
19-43769453-G-A			Likely benign (Jan 19, 2024)
19-43769473-G-T		KCNN4-related disorder	Conflicting classifications of pathogenicity (Nov 14, 2023)
19-43769484-G-A		Dehydrated hereditary stomatocytosis 2	Uncertain significance (Apr 09, 2021)
19-43769490-G-A		Inborn genetic diseases	Uncertain significance (May 28, 2024)
19-43769501-G-A			Likely benign (Mar 14, 2023)
19-43769503-G-A			Uncertain significance (May 27, 2022)
19-43769521-T-C		Inborn genetic diseases • Dehydrated hereditary stomatocytosis 2	Uncertain significance (Feb 13, 2023)
19-43769541-C-T			Uncertain significance (Jul 29, 2022)
19-43769549-G-A			Benign (Nov 28, 2023)
19-43769551-A-G		Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema	Pathogenic (Aug 28, 2020)
19-43769721-C-T		Inborn genetic diseases	Uncertain significance (Dec 01, 2022)
19-43769731-C-T			Likely benign (Mar 01, 2023)
19-43769745-T-A		Dehydrated hereditary stomatocytosis 2 • KCNN4-related disorder	Uncertain significance (Jun 29, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KCNN4	protein_coding	protein_coding	ENST00000262888	8	14725

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.03e-7	0.860	125494	2	251	125747	0.00101

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.62	194	269	0.721	0.0000159	2695
Missense in Polyphen		63	99.913	0.63055		1044
Synonymous	0.755	108	118	0.912	0.00000688	936
Loss of Function	1.53	13	20.5	0.634	0.00000111	202

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0115	0.0114
Ashkenazi Jewish	0.000497	0.000496
East Asian	0.000130	0.000109
Finnish	0.000231	0.000231
European (Non-Finnish)	0.000238	0.000229
Middle Eastern	0.000130	0.000109
South Asian	0.000164	0.000163
Other	0.000660	0.000652

dbNSFP

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.
• Pathway: 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;Polycystic Kidney Disease Pathway;Neuronal System;Ca2+ activated K+ channels;Potassium Channels (Consensus)

Intolerance Scores

• loftool: 0.152
• rvis_EVS: -0.12
• rvis_percentile_EVS: 45.13

Haploinsufficiency Scores

• pHI: 0.168
• hipred: N
• hipred_score: 0.394
• ghis: 0.499

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.600

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kcnn4
• Phenotype: hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); immune system phenotype; renal/urinary system phenotype; digestive/alimentary phenotype; endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; muscle phenotype

Gene ontology

• Biological process: immune system process;potassium ion transport;calcium ion transport;cell volume homeostasis;defense response;stabilization of membrane potential;phospholipid translocation;saliva secretion;positive regulation of protein secretion;positive regulation of T cell receptor signaling pathway;potassium ion transmembrane transport
• Cellular component: plasma membrane;voltage-gated potassium channel complex;vesicle;neuron projection;neuronal cell body
• Molecular function: potassium channel activity;protein binding;calmodulin binding;calcium-activated potassium channel activity;small conductance calcium-activated potassium channel activity;protein phosphatase binding;Intermediate conductance calcium-activated potassium channel activity