ITPR2

protein-coding

inositol 1,4,5-trisphosphate receptor type 2, the group of Inositol 1,4,5-triphosphate receptors|Cilia and flagella associated

Gene summary

The protein encoded by this gene belongs to the inositol 1,4,5-triphosphate receptor family, whose members are second messenger intracellular calcium release channels. These proteins mediate a rise in cytoplasmic calcium in response to receptor activated production of inositol triphosphate. Inositol triphosphate receptor-mediated signaling is involved in many processes including cell migration, cell division, smooth muscle contraction, and neuronal signaling. This protein is a type 2 receptor that consists of a cytoplasmic amino-terminus that binds inositol triphosphate, six membrane-spanning helices that contribute to the ion pore, and a short cytoplasmic carboxy-terminus. A mutation in this gene has been associated with anhidrosis, suggesting that intracellular calcium release mediated by this protein is required for eccrine sweat production. [provided by RefSeq, Apr 2015]

MANE transcript

NM_002223.4

Inheritance

ClinVar variants

P:2U:294B:45

Top phenotype

Anhidrosis, isolated, with normal sweat glands (Dann-Epstein-Sohar syndrome)

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr12:26,335,352-26,833,194

External References & Databases

Ensembl (ENSG00000123104)

Transcript & Mutation Effects

hg38 • Region Span ~497.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

isolated anhidrosis with normal sweat glandsLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0007118

Submitter: Labcorp Genetics (formerly Invitae)

isolated anhidrosis with normal sweat glandsSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007118

Submitter: Orphanet

Clinical Genomic Database (CGD)

Anhidrosis, isolated, with normal sweat glands (Dann-Epstein-Sohar syndrome)AR

Manifestation: Dermatologic

Intervention: Dermatologic

Rationale: Individuals have been described as manifesting with severe heat intolerance, and awareness can allow measures to help control temperature in order to decrease potential sequelae

Refs: 25329695

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ITPR2 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 287

not providedTotal: 28

ITPR2-related disorderTotal: 18

Isolated anhidrosis with normal sweat glandsTotal: 6

Intellectual disabilityTotal: 1

Familial hypercholesterolemiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002223.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	28 clinvar	4 clinvar	35
missense	1 clinvar		285 clinvar	12 clinvar	1 clinvar	299
nonsense			1 clinvar			1
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	2	0	294	40	5	341

Highest pathogenic variant AF is 0.000004796321

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002223.4	RefSeq	NP_002214.2	57	MANE Select
ENST00000381340.8	Ensembl	ENSP00000370744.3	57	MANE Select
NM_001414174.1	RefSeq	NP_001401103.1	57	Standard
NM_001414175.1	RefSeq	NP_001401104.1	55	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
Platelet activation - Homo sapiens (human)
Cortisol synthesis and secretion - Homo sapiens (human)
Aldosterone synthesis and secretion - Homo sapiens (human)
Oxytocin signaling pathway - Homo sapiens (human)

Biological Process

response to hypoxia
signal transduction
platelet activation
inositol phosphate-mediated signaling
regulation of insulin secretion

Molecular Function

inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity
calcium ion binding
calcium ion transmembrane transporter activity
phosphatidylinositol binding
inositol 1,4,5 trisphosphate binding

Cellular Component

nucleus
endoplasmic reticulum
endoplasmic reticulum membrane
plasma membrane
cell cortex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000381340
Coding exons: 57
Length: 495790
Individuals with no LoFs: 124656
Homozygous LoFs: 0
Heterozygous LoFs: 146
Defined: 124802
p: 0.000585

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.71	1030	1.42e+3	0.723	0.0000750	17914
Missense (PolyPhen)		244	460.39	0.52999		5940
Synonymous	-0.618	541	523	1.03	0.0000291	4943
Loss of Function	5.45	71	141	0.505	0.00000763	1755

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00039	0.00039	rare
Latino/Admixed American	0.00071	0.00067	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00045	0.00045	rare
Finnish	0.00033	0.00032	rare
European (Non-Finnish)	0.00064	0.00063	rare
South Asian	0.00089	0.00085	rare
Other	0.00084	0.00082	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium. This release is regulated by cAMP both dependently and independently of PKA (By similarity). {ECO:0000250|UniProtKB:Q9Z329}.;
Disease: DISEASE: Anhidrosis, isolated, with normal sweat glands (ANHD) [MIM:106190]: An autosomal recessive disorder characterized by generalized, isolated anhidrosis, severe heat intolerance, and morphologically normal eccrine sweat glands. Body growth, teeth, hair, nails, and skin are normal. {ECO:0000269|PubMed:25329695}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.206

Intolerance Scores

LoFtool: 0.139
RVIS EVS: -1.64
RVIS percentile EVS: 2.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.726

Gene Damage Prediction

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