TRPC3

protein-coding

transient receptor potential cation channel subfamily C member 3, the group of Transient receptor potential cation channels|Ankyrin repeat domain containing

Gene summary

The protein encoded by this gene is a membrane protein that can form a non-selective channel permeable to calcium and other cations. The encoded protein appears to be induced to form channels by a receptor tyrosine kinase-activated phosphatidylinositol second messenger system and also by depletion of intracellular calcium stores. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

MANE transcript

NM_001130698.2

Inheritance

ClinVar variants

P:1U:130B:66

Top phenotype

Spinocerebellar ataxia 41

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr4:121,874,481-121,952,060

External References & Databases

Ensembl (ENSG00000138741)

Transcript & Mutation Effects

hg38 • Region Span ~77.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia type 41SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014626

Submitter: Orphanet

spinocerebellar ataxia type 41MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014626

Submitter: PanelApp Australia

spinocerebellar ataxia type 41LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014626

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 41AD

Manifestation: 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: 25477146

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRPC3 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 157

not specifiedTotal: 66

TRPC3-related disorderTotal: 11

Spinocerebellar ataxia type 41Total: 11

Essential tremorTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001130698.2. 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				58 clinvar	4 clinvar	62
missense			126 clinvar	2 clinvar	2 clinvar	130
nonsense			3 clinvar			3
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	0	130	60	6	197

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001130698.2	RefSeq	NP_001124170.1	12	MANE Select
ENST00000379645.8	Ensembl	ENSP00000368966.3	12	MANE Select
NM_001366479.2	RefSeq	NP_001353408.1	11	Standard
NM_003305.2	RefSeq	NP_003296.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Axon guidance - Homo sapiens (human)
BDNF-TrkB Signaling
Signaling by GPCR
Signal Transduction
ion channels and their functional role in vascular endothelium

Biological Process

calcium ion transport
manganese ion transport
single fertilization
phototransduction
positive regulation of calcium ion transport into cytosol

Molecular Function

calcium channel activity
protein binding
store-operated calcium channel activity
inositol 1,4,5 trisphosphate binding

Cellular Component

plasma membrane
integral component of plasma membrane
cation channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379645
Coding exons: 12
Length: 72728
Individuals with no LoFs: 125691
Homozygous LoFs: 0
Heterozygous LoFs: 57
Defined: 125748
p: 0.000227

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.84	267	512	0.522	0.0000303	6053
Missense (PolyPhen)		69	188.07	0.36689		2048
Synonymous	1.37	180	205	0.878	0.0000138	1758
Loss of Function	3.01	18	38.0	0.473	0.00000196	470

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.0013	0.0013	notable
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Thought to form a receptor-activated non-selective calcium permeant cation channel. Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C, and by inositol 1,4,5- triphosphate receptors (ITPR) with bound IP3. May also be activated by internal calcium store depletion. {ECO:0000269|PubMed:20095964, ECO:0000269|PubMed:8646775, ECO:0000269|PubMed:9417057, ECO:0000269|PubMed:9930701}.;

Recessive Scores

pRec: 0.246

Intolerance Scores

LoFtool: 0.195
RVIS EVS: -1.24
RVIS percentile EVS: 5.41

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.762

Gene Damage Prediction

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