TRPA1

protein-coding

transient receptor potential cation channel subfamily A member 1, the group of Ankyrin repeat domain containing|Transient receptor potential cation channels

Gene summary

The structure of the protein encoded by this gene is highly related to both the protein ankyrin and transmembrane proteins. The specific function of this protein has not yet been determined; however, studies indicate the function may involve a role in signal transduction and growth control. [provided by RefSeq, Jul 2008]

Previous symbols:

ANKTM1

MANE transcript

NM_007332.3

Inheritance

ClinVar variants

P:1U:148B:65

Top phenotype

Episodic pain syndrome, familial, 1

gnomAD constraint

pLI —, LoF o/e 0.92

Max pathogenic AF

—

Genomic locus

chr8:72,019,917-72,075,584

External References & Databases

Ensembl (ENSG00000104321)

Transcript & Mutation Effects

hg38 • Region Span ~55.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary peripheral neuropathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0020127

Submitter: Ambry Genetics

familial episodic pain syndrome with predominantly upper body involvementLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014021

Submitter: Ambry Genetics

familial episodic pain syndrome with predominantly upper body involvementMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014021

Submitter: PanelApp Australia

familial episodic pain syndrome with predominantly upper body involvementLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014021

Submitter: Labcorp Genetics (formerly Invitae)

familial episodic pain syndrome with predominantly upper body involvementSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014021

Submitter: Orphanet

Clinical Genomic Database (CGD)

Episodic pain syndrome, familial, 1AD

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

Comments: Individuals have been described as suffering from episodes of severe pain that could, to some extent, be predicted and ameliorated, but it is unclear if genetic diagnosis would be additionally advantageous (in addition to clinical diagnosis)

Refs: 20547126

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRPA1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 156

not providedTotal: 52

TRPA1-related disorderTotal: 19

Familial episodic pain syndrome with predominantly upper body involvementTotal: 13

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007332.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	28 clinvar	3 clinvar	34
missense	1 clinvar		128 clinvar	28 clinvar	3 clinvar	160
nonsense			3 clinvar	3 clinvar		6
start loss						0
frameshift			9 clinvar			9
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	1	0	148	59	6	214

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007332.3	RefSeq	NP_015628.2	27	MANE Select
ENST00000262209.5	Ensembl	ENSP00000262209.4	27	MANE Select
ENST00000523582.5	Ensembl	ENSP00000428151.1	24	Standard
ENST00000859810.1	Ensembl	ENSP00000529869.1	27	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
trpa1b	Danio rerio	Structure: chemosensory behavior Quality: decreased occurrence abnormal

Gene / Model

Organism

Observed Phenotype

trpa1b

Danio rerio

Structure: chemosensory behavior

Quality: decreased occurrence

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
Stimuli-sensing channels
Ion channel transport
Transport of small molecules
TRP channels

Biological Process

ion transport
cell surface receptor signaling pathway
response to cold
response to organic substance
response to organic cyclic compound

Molecular Function

calcium channel activity
channel activity
calcium-release channel activity
identical protein binding
temperature-gated cation channel activity

Cellular Component

plasma membrane
integral component of plasma membrane
stereocilium bundle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262209
Coding exons: 27
Length: 55701
Individuals with no LoFs: 125436
Homozygous LoFs: 1
Heterozygous LoFs: 311
Defined: 125748
p: 0.00124

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0357	592	594	0.996	0.0000293	7478
Missense (PolyPhen)		200	208.96	0.9571		2717
Synonymous	-0.718	222	209	1.06	0.0000111	1996
Loss of Function	0.540	55	59.5	0.925	0.00000304	731

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00094	0.00092	rare
Latino/Admixed American	0.00058	0.00058	rare
Ashkenazi Jewish	0.00060	0.00040	rare
East Asian	0.00099	0.00098	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.0014	0.0014	notable
South Asian	0.0030	0.0029	notable
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, cinnamaldehyde, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes (PubMed:25389312, PubMed:20547126). Is also activated by menthol (in vitro)(PubMed:25389312). Acts also as a ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (PubMed:25389312). May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity). {ECO:0000250|UniProtKB:Q8BLA8, ECO:0000269|PubMed:20547126, ECO:0000269|PubMed:25389312, ECO:0000269|PubMed:25855297}.;
Disease: DISEASE: Episodic pain syndrome, familial, 1 (FEPS1) [MIM:615040]: An autosomal dominant neurologic disorder characterized by onset in infancy of episodic debilitating upper body pain triggered by fasting, cold, and physical stress. The period of intense pain is accompanied by breathing difficulties, tachycardia, sweating, generalized pallor, peribuccal cyanosis, and stiffness of the abdominal wall. Affected individuals do not manifest altered pain sensitivity outside the episodes. {ECO:0000269|PubMed:20547126}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.662
RVIS EVS: 0.79
RVIS percentile EVS: 87.29

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.694

Gene Damage Prediction

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