KCNN3

protein-coding

potassium calcium-activated channel subfamily N member 3, the group of Potassium calcium-activated channels

Gene summary

Action potentials in vertebrate neurons are followed by an afterhyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. This gene belongs to the KCNN family of potassium channels. It encodes an integral membrane protein that forms a voltage-independent calcium-activated channel, which is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. This gene contains two CAG repeat regions in the coding sequence. It was thought that expansion of one or both of these repeats could lead to an increased susceptibility to schizophrenia or bipolar disorder, but studies indicate that this is probably not the case. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

MANE transcript

NM_002249.6

Inheritance

AD, AR

ClinVar variants

P:5U:109B:34

Top phenotype

Zimmermann-Laband syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr1:154,697,455-154,870,281

External References & Databases

Ensembl (ENSG00000143603)

Transcript & Mutation Effects

hg38 • Region Span ~172.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Zimmermann-Laband syndrome 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032854

Submitter: G2P

Zimmermann-Laband syndrome 3MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032854

Submitter: Ambry Genetics

Zimmermann-Laband syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000200

Submitter: Orphanet

Zimmermann-Laband syndrome 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032854

Submitter: PanelApp Australia

schizophreniaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0005090

Submitter: Labcorp Genetics (formerly Invitae)

Zimmermann-Laband syndrome 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032854

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Zimmermann-Laband syndrome 3AD

Manifestation: Craniofacial; Dental; Dermatologic; Musculoskeletal; 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: 31155282

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNN3 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 71

Inborn genetic diseasesTotal: 59

not specifiedTotal: 27

Zimmermann-Laband syndrome 3Total: 22

KCNN3-related disorderTotal: 4

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002249.6. 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			1 clinvar	15 clinvar		16
missense	3 clinvar	2 clinvar	98 clinvar	19 clinvar		122
nonsense			4 clinvar			4
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	3	2	109	34	0	148

Highest pathogenic variant AF is 0.00021241316

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002249.6	RefSeq	NP_002240.3	8	MANE Select
ENST00000271915.9	Ensembl	ENSP00000271915.3	8	MANE Select
NM_001204087.2	RefSeq	NP_001191016.1	9	Standard
NM_001365837.1	RefSeq	NP_001352766.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Insulin secretion - Homo sapiens (human)
Neuronal System
Ca2+ activated K+ channels
Potassium Channels

Biological Process

potassium ion transmembrane transport

Molecular Function

calmodulin binding
small conductance calcium-activated potassium channel activity

Cellular Component

plasma membrane
integral component of membrane
neuron projection
neuronal cell body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000271915
Coding exons: 8
Length: 172826
Individuals with no LoFs: 125703
Homozygous LoFs: 32
Heterozygous LoFs: 13
Defined: 125748
p: 0.000179

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.33	245	442	0.555	0.0000265	4808
Missense (PolyPhen)		66	152.56	0.43262		1753
Synonymous	0.221	190	194	0.980	0.0000127	1494
Loss of Function	4.27	4	28.7	0.139	0.00000152	283

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00098	0.00023	rare
Ashkenazi Jewish	0.00088	0.00020	rare
East Asian	0.00091	0.00027	rare
Finnish	0.00035	0.00018	rare
European (Non-Finnish)	0.00038	0.00012	rare
South Asian	0.0013	0.00029	notable
Other	0.0023	0.00049	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Forms a voltage-independent potassium channel activated by intracellular calcium. Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization. The channel is blocked by apamin.;

Recessive Scores

pRec: 0.156

Intolerance Scores

LoFtool: 0.0697
RVIS EVS: -0.56
RVIS percentile EVS: 19.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.329

Gene Damage Prediction

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