HTR2A

protein-coding

5-hydroxytryptamine receptor 2A, the group of 5-hydroxytryptamine receptors, G protein-coupled

Gene summary

This gene encodes one of the receptors for serotonin, a neurotransmitter with many roles. Mutations in this gene are associated with susceptibility to schizophrenia and obsessive-compulsive disorder, and are also associated with response to the antidepressant citalopram in patients with major depressive disorder (MDD). MDD patients who also have a mutation in intron 2 of this gene show a significantly reduced response to citalopram as this antidepressant downregulates expression of this gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

Previous symbols:

HTR2

MANE transcript

NM_000621.5

Inheritance

ClinVar variants

U:32B:11

Top phenotype

Major depressive disorder, response to citalopram therapy in; Clozapine, response to

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr13:46,831,546-46,897,076

External References & Databases

Ensembl (ENSG00000102468)

Transcript & Mutation Effects

hg38 • Region Span ~65.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

Major depressive disorder, response to citalopram therapy in; Clozapine, response toAD

Manifestation: General

Intervention: Pharmacogenomic

Rationale: Variants may relate to the efficacy of medications such as Citalopram and clozapine

Refs: 9491814; 12563180; 16642436

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HTR2A variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 31

not providedTotal: 10

HTR2A-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000621.5. 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	9 clinvar	1 clinvar	11
missense			30 clinvar	1 clinvar		31
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	32	10	1	43

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000621.5	RefSeq	NP_000612.1	3	MANE Select
ENST00000542664.4	Ensembl	ENSP00000437737.1	3	MANE Select
NM_001165947.5	RefSeq	NP_001159419.2	2	Standard
NM_001378924.1	RefSeq	NP_001365853.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
htr2ab	Danio rerio	Structure: commissure of the tract of the commissure of the caudal tuberculum Quality: decreased process quality abnormal

Gene / Model

Organism

Observed Phenotype

htr2ab

Danio rerio

Structure: commissure of the tract of the commissure of the caudal tuberculum

Quality: decreased process quality

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)
Serotonergic synapse - Homo sapiens (human)
Gap junction - Homo sapiens (human)
Calcium signaling pathway - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)

Biological Process

temperature homeostasis
cellular calcium ion homeostasis
G protein-coupled receptor signaling pathway
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
phospholipase C-activating G protein-coupled receptor signaling pathway

Molecular Function

virus receptor activity
G-protein alpha-subunit binding
G protein-coupled receptor activity
G protein-coupled serotonin receptor activity
drug binding

Cellular Component

cytosol
plasma membrane
integral component of plasma membrane
caveola
axon

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378688
Coding exons: 3
Length: 65485
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.75	177	256	0.692	0.0000145	3083
Missense (PolyPhen)		54	115.73	0.46661		1386
Synonymous	-0.147	109	107	1.02	0.00000670	935
Loss of Function	2.86	3	14.9	0.201	7.07e-7	189

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: G-protein coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:1330647, PubMed:18703043, PubMed:19057895). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4- iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD) (PubMed:28129538). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors (PubMed:28129538). Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways (PubMed:28129538). Signaling activates phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca(2+) ions from intracellular stores (PubMed:18703043, PubMed:28129538). Affects neural activity, perception, cognition and mood (PubMed:18297054). Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction. {ECO:0000269|PubMed:1330647, ECO:0000269|PubMed:18297054, ECO:0000269|PubMed:18703043, ECO:0000269|PubMed:19057895, ECO:0000269|PubMed:21645528, ECO:0000269|PubMed:22300836, ECO:0000269|PubMed:28129538}.;

Recessive Scores

pRec: 0.342

Intolerance Scores

LoFtool: 0.186
RVIS EVS: 0.44
RVIS percentile EVS: 77.8

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.621

Gene Damage Prediction

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