ANO2

Summary

ANO2 (anoctamin 2, HGNC:1183) is a protein-coding gene on chromosome 12p13.31, encoding Anoctamin-2 (Q9NQ90). Calcium-activated chloride channel (CaCC) which may play a role in olfactory signal transduction.

ANO2 belongs to a family of calcium-activated chloride channels (CaCCs) (reviewed by Hartzell et al., 2009 [PubMed 19015192]).

Source: NCBI Gene 57101 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 30 total — 2 pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_001364791

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1183
Approved symbol	ANO2
Name	anoctamin 2
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000047617
Ensembl biotype	protein_coding
OMIM	610109
Entrez	57101

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding_CDS_not_defined, 4 protein_coding

ENST00000356134, ENST00000536751, ENST00000538154, ENST00000540543, ENST00000541487, ENST00000541874, ENST00000542326, ENST00000544988, ENST00000545860, ENST00000650848, ENST00000682330

RefSeq mRNA: 3 — MANE Select: NM_001364791 NM_001278596, NM_001278597, NM_001364791

CCDS: CCDS44807, CCDS91642, CCDS91643

Canonical transcript exons

ENST00000682330 — 25 exons

Exon	Start	End
ENSE00000369645	5575834	5576015
ENSE00000714392	5565558	5565663
ENSE00000714393	5577955	5578007
ENSE00000714395	5599484	5599629
ENSE00000714434	5615186	5615297
ENSE00000714440	5744157	5744317
ENSE00000714441	5750836	5750970
ENSE00000714442	5799507	5799571
ENSE00000714454	5806052	5806093
ENSE00001043579	5635152	5635347
ENSE00001167065	5807313	5807368
ENSE00001296413	5921040	5921366
ENSE00001302307	5827769	5827820
ENSE00001314561	5922620	5922804
ENSE00001649282	5578366	5578518
ENSE00003475792	5647727	5647801
ENSE00003483300	5612656	5612756
ENSE00003506281	5732520	5732630
ENSE00003548353	5612901	5612958
ENSE00003559502	5830435	5830489
ENSE00003563197	5739317	5739399
ENSE00003656372	5854043	5854141
ENSE00003671636	5832452	5832603
ENSE00003720946	5945196	5945259
ENSE00003919205	5562655	5563568

Expression profiles

Bgee: expression breadth ubiquitous, 165 present calls, max score 89.19.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3565 / max 122.5880, expressed in 101 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129038	0.2155	75
129039	0.1116	23
129035	0.0294	11

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	89.19	gold quality
left testis	UBERON:0004533	86.43	gold quality
calcaneal tendon	UBERON:0003701	86.17	gold quality
right testis	UBERON:0004534	85.94	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.84	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.77	gold quality
testis	UBERON:0000473	82.37	gold quality
apex of heart	UBERON:0002098	82.21	gold quality
omental fat pad	UBERON:0010414	81.91	gold quality
peritoneum	UBERON:0002358	81.80	gold quality
right lung	UBERON:0002167	80.66	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.84	gold quality
upper lobe of left lung	UBERON:0008952	77.91	gold quality
right atrium auricular region	UBERON:0006631	76.51	gold quality
heart left ventricle	UBERON:0002084	76.29	gold quality
upper lobe of lung	UBERON:0008948	75.84	gold quality
endocervix	UBERON:0000458	75.41	gold quality
subcutaneous adipose tissue	UBERON:0002190	75.21	gold quality
cardiac ventricle	UBERON:0002082	75.15	gold quality
tendon	UBERON:0000043	75.14	gold quality
ectocervix	UBERON:0012249	74.69	gold quality
cardiac atrium	UBERON:0002081	74.31	gold quality
heart	UBERON:0000948	73.47	gold quality
mucosa of stomach	UBERON:0001199	72.91	gold quality
left coronary artery	UBERON:0001626	72.52	gold quality
body of uterus	UBERON:0009853	72.51	gold quality
lower esophagus muscularis layer	UBERON:0035833	72.41	gold quality
lower esophagus	UBERON:0013473	72.34	gold quality
right coronary artery	UBERON:0001625	72.26	gold quality
adipose tissue	UBERON:0001013	71.92	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	2693.27
E-HCAD-35	yes	22.03
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXA2, MYCN

Literature-anchored findings (GeneRIF, showing 13)

• C12orf3, FLJ10261 (ORAOV2), C11orf25 and FLJ34272 constitute a family of eight-transmembrane proteins with N- and C-terminal tails facing the cytoplasm. (PMID:12739008)
• VWF and TMEM16B deletions may have a role in severe von Willebrand disease type 3 (PMID:17371490)
• This study suggested that TMEM16B to be a strong candidate for the long sought-after Ca(2+)-dependent chloride channel in the photoreceptor synapse. (PMID:19474308)
• Ano2 likely amplifies the odor-induced generator potential in olfactory sensory neuron cilia by sensing elevated calcium levels, permitting the outward flow of chloride ions from the cell. (PMID:19561302)
• The third intracellular loop of TMEM16B is the site involved in calcium ion sensitivity, whereas the C-terminal part affects the rate of transition between the open and the closed state of the channel. (PMID:23570556)
• ANO2 is present in human myometrium. (PMID:24928056)
• results reveal multidimensional regulation of TMEM16A/16B by preassociated apoCaM and introduce ChIMP as a versatile tool to probe the macromolecular complex and function of Ca(2+)-activated chloride channels (PMID:25489088)
• Olfactory function impairment in Italian patients with type 3 von Willebrand disease with partial deletion of TMEM16B. (PMID:25635880)
• data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in multiple sclerosis cases compared with controls (PMID:26862169)
• residues facing the putative channel pore are responsible both for controlling the ion selectivity and the gating of the channel, providing an initial understanding of molecular mechanism of ion permeation in TMEM16B (PMID:28046119)
• a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of Multiple sclerosis. (PMID:31375628)
• Anoctamin 2-chloride channels reduce simple spike activity and mediate inhibition at elevated calcium concentration in cerebellar Purkinje cells. (PMID:33651839)
• Modulation of TMEM16B channel activity by the calcium-activated chloride channel regulator 4 (CLCA4) in human cells. (PMID:38825009)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ano2a	ENSDARG00000003210
danio_rerio	ano2b	ENSDARG00000101363
danio_rerio		ENSDARG00000112349
mus_musculus	Ano2	ENSMUSG00000038115
rattus_norvegicus	Ano2	ENSRNOG00000023561

Paralogs (10): ANO8 (ENSG00000074855), PPP1R7 (ENSG00000115685), ANO1 (ENSG00000131620), ANO3 (ENSG00000134343), ANO7 (ENSG00000146205), ANO4 (ENSG00000151572), ANO10 (ENSG00000160746), ANO5 (ENSG00000171714), ANO6 (ENSG00000177119), ANO9 (ENSG00000185101)

Protein

Protein identifiers

Anoctamin-2 — Q9NQ90 (reviewed: Q9NQ90)

Alternative names: Transmembrane protein 16B

All UniProt accessions (3): A0A804HIY3, F5H806, Q9NQ90

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-activated chloride channel (CaCC) which may play a role in olfactory signal transduction. Odorant molecules bind to odor-sensing receptors (OSRs), leading to an increase in calcium entry that activates CaCC current which amplifies the depolarization of the OSR cells, ANO2 seems to be the underlying chloride channel involved in this process. May mediate light perception amplification in retina.

Subunit / interactions. Homodimer. Component of a presynaptic protein complex recruited to specialized plasma membrane domains of photoreceptors. Interacts with DLG4 by its C-terminal region.

Subcellular location. Cell membrane.

Tissue specificity. Retina, especially in the photoreceptor synaptic terminals.

Activity regulation. Channel activity is repressed by chloride inhibitors; strongly by niflumic acid (NFA), partially by flufenamic acid (FFA), and only slightly by meclofenamic acid (MFA), 5-Nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), 4-acetamido-4’-isothiocyanato-stilben-2,2’-disulfonate (SITS), and 4,4’-diisothiocyanatostilbene-2,2’-disulfonic acid (DIDS).

Miscellaneous. The term ‘anoctamin’ was coined because these channels are anion selective and have eight (OCT) transmembrane segments. There is some dissatisfaction in the field with the Ano nomenclature because it is not certain that all the members of this family are anion channels or have the 8-transmembrane topology. Splice site between exons 4 and 5 is non-canonical. Splice site between exons 4 and 5 is non-canonical. A molecular mimicry between ANO2 and Epstein-Barr virus EBNA1 could possibly be linked to multiple sclerosis in the host.

Similarity. Belongs to the anoctamin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NQ90-4	1	yes
Q9NQ90-1	2
Q9NQ90-2	3

RefSeq proteins (3): NP_001265525, NP_001265526, NP_001351720* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007632	Anoctamin	Family
IPR032394	Anoct_dimer	Domain
IPR049452	Anoctamin_TM	Domain

Pfam: PF04547, PF16178

Catalyzed reactions (Rhea), 1 shown:

• chloride(in) = chloride(out) (RHEA:29823)

UniProt features (32 total): topological domain 9, transmembrane region 8, glycosylation site 4, sequence variant 4, splice variant 3, chain 1, region of interest 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQ90-F1	74.81	0.26

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (4): 421, 836, 844, 851

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-381753	Olfactory Signaling Pathway
R-HSA-9733458	Induction of Cell-Cell Fusion
R-HSA-1643685	Disease
R-HSA-382551	Transport of small molecules
R-HSA-5663205	Infectious disease
R-HSA-9679506	SARS-CoV Infections
R-HSA-9694516	SARS-CoV-2 Infection
R-HSA-9709957	Sensory Perception
R-HSA-9772573	Late SARS-CoV-2 Infection Events
R-HSA-9824446	Viral Infection Pathways
R-HSA-983712	Ion channel transport

MSigDB gene sets: 76 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_CHLORIDE_TRANSPORT, GOBP_TRANSMEMBRANE_TRANSPORT, SHEN_SMARCA2_TARGETS_DN, SENESE_HDAC3_TARGETS_DN, GOCC_CHLORIDE_CHANNEL_COMPLEX, GOCC_TRANSPORTER_COMPLEX, GOCC_MEMBRANE_PROTEIN_COMPLEX, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_GATED_CHANNEL_ACTIVITY, GOMF_PASSIVE_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_MONOATOMIC_ANION_CHANNEL_ACTIVITY, GOMF_MONOATOMIC_ANION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_TRANSPORTER_ACTIVITY

GO Biological Process (5): monoatomic ion transmembrane transport (GO:0034220), chloride transmembrane transport (GO:1902476), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), establishment of localization in cell (GO:0051649)

GO Molecular Function (5): intracellularly calcium-gated chloride channel activity (GO:0005229), chloride channel activity (GO:0005254), protein dimerization activity (GO:0046983), protein binding (GO:0005515), identical protein binding (GO:0042802)

GO Cellular Component (8): nucleoplasm (GO:0005654), plasma membrane (GO:0005886), chloride channel complex (GO:0034707), membrane (GO:0016020), presynaptic membrane (GO:0042734), neuron projection (GO:0043005), non-motile cilium (GO:0097730), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Ion channel transport	1
Sensory Perception	1
Late SARS-CoV-2 Infection Events	1
Disease	1
Viral Infection Pathways	1
SARS-CoV Infections	1
SARS-CoV-2 Infection	1
Infectious disease	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	2
cellular anatomical structure	2
monoatomic ion transport	1
transmembrane transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
transport	1
monoatomic anion transport	1
inorganic anion transport	1
establishment of localization	1
cellular localization	1
chloride channel activity	1
ligand-gated monoatomic anion channel activity	1
intracellularly calcium-gated channel activity	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
binding	1
nuclear lumen	1
membrane	1
cell periphery	1
monoatomic ion channel complex	1
synaptic membrane	1
presynapse	1
plasma membrane bounded cell projection	1
cilium	1
synapse	1

Protein interactions and networks

STRING

760 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANO2	CLCA4	Q14CN2	984
ANO2	CLCA2	Q9UQC9	973
ANO2	CLCA1	A8K7I4	933
ANO2	CNGA2	Q16280	764
ANO2	CNGA4	Q8IV77	629
ANO2	ANO1	Q5XXA6	626
ANO2	RTP2	Q5QGT7	614
ANO2	ADCY3	O60266	561
ANO2	ALS2CL	Q60I27	560
ANO2	CALML3	P27482	549
ANO2	CALML4	Q96GE6	541
ANO2	CALML5	Q9NZT1	537
ANO2	CALM1	P02593	535
ANO2	CALML6	Q8TD86	534
ANO2	OMP	P47874	531

IntAct

3 interactions, top by confidence:

A	B	Type	Score
DLG1	ANO2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (2): ANO2 (Affinity Capture-RNA), ANO2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IQZ2, A0MFS9, A2WV32, A2YMH5, A5WVX9, A8Y2U2, F1RAX4, F4HVJ3, F4JIN3, G5ECD6, G5ED05, O13621, O17386, O18304, O45363, O48947, O62136, O74737, P0C5E7, P34319, P34389, P34577, Q0JJZ6, Q10287, Q10436, Q21412, Q22566, Q23027, Q23369, Q4KMQ2, Q4R690, Q5JN63, Q5NVB9, Q5XXA6, Q6ZF85, Q84JA6, Q8BHY3, Q8CFW1, Q8IUH4, Q8L778

Diamond homologs: A1A5B4, A2AHL1, A6QLE6, P86044, Q14AT5, Q32M45, Q4KMQ2, Q5XXA6, Q6IFT6, Q6IWH7, Q6P9J9, Q75UR0, Q75V66, Q8BHY3, Q8C5H1, Q8CFW1, Q9BYT9, Q9NQ90, Q6PB70, Q9HCE9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

30 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	4
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1330180	GRCh37/hg19 12p13.33-13.31(chr12:146240-8330229)x3	Pathogenic
1527679	GRCh37/hg19 12p13.31(chr12:6024262-6276970)	Pathogenic

SpliceAI

5929 predictions. Top by Δscore:

Variant	Effect	Δscore
12:5563564:AGGTT:A	acceptor_gain	1.0000
12:5563565:GGTT:G	acceptor_gain	1.0000
12:5563566:GTT:G	acceptor_gain	1.0000
12:5563567:TT:T	acceptor_gain	1.0000
12:5563567:TTCTG:T	acceptor_loss	1.0000
12:5563568:TCT:T	acceptor_loss	1.0000
12:5563569:C:CC	acceptor_gain	1.0000
12:5563572:C:CT	acceptor_gain	1.0000
12:5563573:A:T	acceptor_gain	1.0000
12:5578516:TGA:T	acceptor_gain	1.0000
12:5578519:C:CC	acceptor_gain	1.0000
12:5599482:A:AC	donor_gain	1.0000
12:5599482:ACT:A	donor_gain	1.0000
12:5599483:C:CA	donor_gain	1.0000
12:5599483:CT:C	donor_gain	1.0000
12:5599483:CTC:C	donor_gain	1.0000
12:5599486:A:AC	donor_gain	1.0000
12:5599486:ATTT:A	donor_gain	1.0000
12:5599486:ATTTC:A	donor_gain	1.0000
12:5599487:T:C	donor_gain	1.0000
12:5599489:T:A	donor_gain	1.0000
12:5599496:A:AC	donor_gain	1.0000
12:5599497:C:CC	donor_gain	1.0000
12:5599499:C:CA	donor_gain	1.0000
12:5599509:T:TA	donor_gain	1.0000
12:5599626:CTTC:C	acceptor_gain	1.0000
12:5599627:TTC:T	acceptor_gain	1.0000
12:5599628:TC:T	acceptor_gain	1.0000
12:5599629:CC:C	acceptor_gain	1.0000
12:5599629:CCT:C	acceptor_loss	1.0000

AlphaMissense

6620 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:5799556:A:G	W337R	1.000
12:5799556:A:T	W337R	1.000
12:5827807:A:G	L286P	1.000
12:5830445:C:G	R278P	1.000
12:5921062:A:G	L171P	1.000
12:5921077:A:G	L166P	1.000
12:5578002:A:G	W803R	0.999
12:5578002:A:T	W803R	0.999
12:5578396:G:C	R791G	0.999
12:5578423:C:G	A782P	0.999
12:5578445:G:C	N774K	0.999
12:5578445:G:T	N774K	0.999
12:5612716:A:G	L681P	0.999
12:5739346:A:G	W470R	0.999
12:5739346:A:T	W470R	0.999
12:5739377:C:A	W459C	0.999
12:5739377:C:G	W459C	0.999
12:5739378:C:G	W459S	0.999
12:5739379:A:G	W459R	0.999
12:5739379:A:T	W459R	0.999
12:5744160:A:G	W451R	0.999
12:5744160:A:T	W451R	0.999
12:5750908:A:G	L374P	0.999
12:5750933:A:G	W366R	0.999
12:5750933:A:T	W366R	0.999
12:5750937:A:C	F364L	0.999
12:5750937:A:T	F364L	0.999
12:5750939:A:G	F364L	0.999
12:5750959:C:A	G357V	0.999
12:5750959:C:T	G357E	0.999

dbSNP variants (sampled 300 via entrez): RS1000005828 (12:5642070 T>C), RS1000010123 (12:5617303 C>T), RS1000015289 (12:5722789 T>C), RS1000026478 (12:5815253 G>C), RS1000030710 (12:5927757 G>C,T), RS1000053481 (12:5798526 A>G), RS1000057208 (12:5919277 G>C), RS1000065727 (12:5898736 T>G), RS1000070820 (12:5923784 C>T), RS1000076511 (12:5885520 C>G), RS1000081438 (12:5615954 C>T), RS1000095804 (12:5766395 C>T), RS1000100311 (12:5846997 T>C), RS1000110549 (12:5660712 T>C), RS1000113431 (12:5623307 C>A)

Disease associations

OMIM: gene MIM:610109 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): obesity disorder (MONDO:0011122)

Orphanet (3): Non-syndromic bicoronal craniosynostosis (Orphanet:35099), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0001513	Obesity

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000320_7	Panic disorder	4.000000e-09
GCST001762_853	Obesity-related traits	3.000000e-06
GCST002925_5	Sex hormone levels	2.000000e-08
GCST003133_3	Plasma clusterin levels	3.000000e-06
GCST004751_25	Serum uric acid levels in response to allopurinol in gout	7.000000e-06
GCST009391_1124	Metabolite levels	5.000000e-06
GCST009542_1	Cleft lip with or without cleft palate x maternal periconceptional alcohol use interaction (parent of origin effect)	7.000000e-06
GCST010703_74	Brain morphology (MOSTest)	3.000000e-08
GCST011038_7	Parkinson’s disease progression (motor)	6.000000e-06

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0003940	physical activity
EFO:0004697	estradiol measurement
EFO:0004730	hormone measurement
EFO:0007656	plasma clusterin measurement
EFO:0004761	uric acid measurement
EFO:0010523	phosphoglyceric acid measurement
EFO:0003959	cleft lip
EFO:0005939	parental genotype effect measurement
EFO:0009113	alcohol exposure measurement
EFO:0004346	neuroimaging measurement
EFO:0008336	disease progression measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105767 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

18 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs17724452	Efficacy	3	duloxetine	Major Depressive Disorder
rs17724464	Efficacy	3	duloxetine	Major Depressive Disorder
rs17724494	Efficacy	3	duloxetine	Major Depressive Disorder
rs17786394	Efficacy	3	duloxetine	Major Depressive Disorder
rs17786400	Efficacy	3	duloxetine	Major Depressive Disorder
rs17786412	Efficacy	3	duloxetine	Major Depressive Disorder
rs61908402	Efficacy	3	duloxetine	Major Depressive Disorder
rs61908403	Efficacy	3	duloxetine	Major Depressive Disorder
rs61908404	Efficacy	3	duloxetine	Major Depressive Disorder
rs61908405	Efficacy	3	duloxetine	Major Depressive Disorder
rs61908406	Efficacy	3	duloxetine	Major Depressive Disorder
rs61908407	Efficacy	3	duloxetine	Major Depressive Disorder
rs61908408	Efficacy	3	duloxetine	Major Depressive Disorder
rs61908409	Efficacy	3	duloxetine	Major Depressive Disorder
rs61908410	Efficacy	3	duloxetine	Major Depressive Disorder
rs61908411	Efficacy	3	duloxetine	Major Depressive Disorder
rs78482393	Efficacy	3	duloxetine	Major Depressive Disorder
rs78615940	Efficacy	3	duloxetine	Major Depressive Disorder

PharmGKB variants

19 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs17724452	ANO2	3	0.00	1	duloxetine
rs17724464	ANO2	3	0.00	1	duloxetine
rs17724494	ANO2	3	0.00	1	duloxetine
rs17786394	ANO2	3	0.00	1	duloxetine
rs17786400	ANO2	3	0.00	1	duloxetine
rs17786412	ANO2	3	0.00	1	duloxetine
rs61908402	ANO2	3	0.00	1	duloxetine
rs61908403	ANO2	3	0.00	1	duloxetine
rs61908404	ANO2	3	0.00	1	duloxetine
rs61908405	ANO2	3	0.00	1	duloxetine
rs61908406	ANO2	3	0.00	1	duloxetine
rs61908407	ANO2	3	0.00	1	duloxetine
rs61908408	ANO2	3	0.00	1	duloxetine
rs61908409	ANO2	3	0.00	1	duloxetine
rs61908410	ANO2	3	0.00	1	duloxetine
rs61908411	ANO2	3	0.00	1	duloxetine
rs78482393	ANO2	3	0.00	1	duloxetine
rs78615940	ANO2	3	0.00	1	duloxetine
rs2110166	ANO2		0.00	0

ChEMBL bioactivities

8 potent at pChembl≥5 of 14 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.40	IC50	400	nM	CHEMBL4071143
6.40	IC50	400	nM	CHEMBL4074929
5.96	IC50	1100	nM	CHEMBL4104024
5.85	IC50	1400	nM	CHEMBL1444023
5.85	IC50	1400	nM	CHEMBL4085154
5.40	IC50	4000	nM	CHEMBL1299863
5.34	IC50	4600	nM	CHEMBL3134585
5.06	IC50	8700	nM	CHEMBL5186789

PubChem BioAssay actives

8 with measured affinity, of 52 total; 8 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(2-bromo-2,2-difluoroacetyl)amino]-N-(2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide	1448056: Inhibition of human TMEM16B expressed in FRT cells co-expressing iodide sensitive fluorescent protein YFP-H148Q/I152L/F46L assessed as reduction in ATP-induced Ca2+ activation-mediated chloride current by measuring decrease in iodide influx preincubated for 10 mins followed by ATP/iodide addition by fluorescence assay	ic50	0.4000	uM
2-[(2-chloro-2,2-difluoroacetyl)amino]-N-(2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide	1448056: Inhibition of human TMEM16B expressed in FRT cells co-expressing iodide sensitive fluorescent protein YFP-H148Q/I152L/F46L assessed as reduction in ATP-induced Ca2+ activation-mediated chloride current by measuring decrease in iodide influx preincubated for 10 mins followed by ATP/iodide addition by fluorescence assay	ic50	0.4000	uM
2-[(2,2-difluoro-2-iodoacetyl)amino]-N-(4-fluorophenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide	1448056: Inhibition of human TMEM16B expressed in FRT cells co-expressing iodide sensitive fluorescent protein YFP-H148Q/I152L/F46L assessed as reduction in ATP-induced Ca2+ activation-mediated chloride current by measuring decrease in iodide influx preincubated for 10 mins followed by ATP/iodide addition by fluorescence assay	ic50	1.1000	uM
N-(2-methylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide	1448056: Inhibition of human TMEM16B expressed in FRT cells co-expressing iodide sensitive fluorescent protein YFP-H148Q/I152L/F46L assessed as reduction in ATP-induced Ca2+ activation-mediated chloride current by measuring decrease in iodide influx preincubated for 10 mins followed by ATP/iodide addition by fluorescence assay	ic50	1.4000	uM
2-[(2,2-difluoro-2-iodoacetyl)amino]-N-(2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide	1448056: Inhibition of human TMEM16B expressed in FRT cells co-expressing iodide sensitive fluorescent protein YFP-H148Q/I152L/F46L assessed as reduction in ATP-induced Ca2+ activation-mediated chloride current by measuring decrease in iodide influx preincubated for 10 mins followed by ATP/iodide addition by fluorescence assay	ic50	1.4000	uM
2-[(5-ethyl-4-methyl-6-oxo-1H-pyrimidin-2-yl)sulfanyl]-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]acetamide	1448075: Inhibition of TMEM16B (unknown origin) expressed in FRT cells assessed as reduction of ATP-induced chloride conductance preincubated for 20 mins followed by ATP addition by short-circuit current assay	ic50	4.0000	uM
N-phenyl-2-[(2,2,2-trifluoroacetyl)amino]-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide	1448056: Inhibition of human TMEM16B expressed in FRT cells co-expressing iodide sensitive fluorescent protein YFP-H148Q/I152L/F46L assessed as reduction in ATP-induced Ca2+ activation-mediated chloride current by measuring decrease in iodide influx preincubated for 10 mins followed by ATP/iodide addition by fluorescence assay	ic50	4.6000	uM
4-(4-chlorophenyl)-2-[(2,5-difluorobenzoyl)amino]thiophene-3-carboxylic acid	1868466: Inhibition of human ANO2 expressed in HEK293 cells incubated for 5 mins by whole cell patch clamp electrophysiology	ic50	8.7000	uM

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression	2
Valproic Acid	decreases expression	2
bisphenol A	decreases methylation, affects cotreatment	1
sulforaphane	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
nickel sulfate	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
Fulvestrant	decreases methylation, affects cotreatment	1
Benzo(a)pyrene	increases methylation	1
Doxorubicin	decreases expression	1
Methapyrilene	increases methylation	1
Methotrexate	decreases expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Aflatoxin B1	affects methylation	1

ChEMBL screening assays

8 unique, capped per target: 5 binding, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4015869	Binding	Inhibition of human TMEM16B expressed in FRT cells co-expressing iodide sensitive fluorescent protein YFP-H148Q/I152L/F46L assessed as reduction in ATP-induced Ca2+ activation-mediated chloride current by measuring decrease in iodide influx	Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A). — J Med Chem
CHEMBL4310425	ADMET	Inhibition of YFP-fused ANO2 (unknown origin) expressed in FRT cells after 20 mins by fluorescence quenching method	Synthesis and biological evaluation of novel Ani9 derivatives as potent and selective ANO1 inhibitors. — Eur J Med Chem

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00076362	PHASE4	COMPLETED	Pediatric Hypothalamic Obesity
NCT00079547	PHASE4	COMPLETED	The Safety and Effectiveness of Low and High Carbohydrate Diets
NCT00115063	PHASE4	TERMINATED	LOSS- Louisiana Obese Subjects Study
NCT00134303	PHASE4	COMPLETED	Trial Comparing Metformin Versus Placebo in Non Alcoholic Steatohepatitis (NASH) Patients Receiving Bariatric Surgery for Obesity
NCT00143936	PHASE4	COMPLETED	The Safety and Efficacy of Low and High Carbohydrate Diets
NCT00143962	PHASE4	COMPLETED	Comparison of Two Approaches to Weight Loss Follow-Up Study
NCT00152360	PHASE4	COMPLETED	The Effect of Xenical on Weight and Risk Factors
NCT00176306	PHASE4	COMPLETED	Levofloxacin Pharmacokinetics (PK) in the Severely Obese
NCT00203450	PHASE4	COMPLETED	Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial
NCT00205504	PHASE4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00229229	PHASE4	TERMINATED	Comparison of 4 Diets in the Management of Overweight Patients With Vascular Disease
NCT00234988	PHASE4	COMPLETED	A Phase IV, Multi-Center, Open-Label Trial of Sibutramine in Combination With a Hypocaloric Diet in Obese and Overweight Thai Subjects.
NCT00264589	PHASE4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00288873	PHASE4	COMPLETED	Characterization of Hyperparathyroidism and Vitamin D Deficiency in Obesity
NCT00298857	PHASE4	TERMINATED	A Pharmacokinetic Study to Compare the Dosing of Valproic Acid in Subjects With Different Body Weights
NCT00315146	PHASE4	COMPLETED	Optimizing Body Composition for Function in Older Adults
NCT00319202	PHASE4	TERMINATED	Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
NCT00327912	PHASE4	UNKNOWN	Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Biliopancreatic Diversion (BPD)- Duodenal Switch for Superobesity
NCT00352287	PHASE4	COMPLETED	Study to Determine the Effects of Human Growth Hormone and Pioglitazone in Overweight, Prediabetic Adults
NCT00353054	PHASE4	COMPLETED	Effect of Calcium/Vitamin D Supplementation on Body Weight and Fat Loss.
NCT00390637	PHASE4	COMPLETED	Diet, Obesity and Genes (DiOGenes)
NCT00415688	PHASE4	COMPLETED	Lifestyle Modification for Obesity-Related Type 2 Diabetes
NCT00433641	PHASE4	COMPLETED	Weight Loss in Response to Sibutramine (MERIDIA) is Influenced by the Inherited Genes
NCT00440375	PHASE4	COMPLETED	Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women
NCT00453557	PHASE4	COMPLETED	Mechanism of Growth Hormone Effects on Adipose Tissue
NCT00456885	PHASE4	COMPLETED	The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women
NCT00463112	PHASE4	COMPLETED	Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS
NCT00512187	PHASE4	COMPLETED	Moderate Weight Loss Makes Obese Patients With Severe Chronic Plaque Psoriasis Responsive to Sub-Optimal Dose of Cyclosporine: an Investigator Blinded, Controlled, Randomized Clinical Trial
NCT00516919	PHASE4	COMPLETED	Study of Behavioral Weight Loss Therapy for Obesity and Binge Eating in Monolingual Hispanic Persons
NCT00522470	PHASE4	COMPLETED	Effects of Rosiglitazone on Serum Ghrelin and Peptide YY Levels
NCT00537810	PHASE4	COMPLETED	Treatment of Binge Eating in Obese Patients in Primary Care
NCT00538486	PHASE4	COMPLETED	A Randomized, Double-Blind, Active Control Trial Comparing Effects of Telmisartan, Candesartan and Amlodipine, Alone or Plus Metformin, on Non-Diabetic, Obese Hypertensive Patients
NCT00584389	PHASE4	TERMINATED	The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition
NCT00585182	PHASE4	COMPLETED	Study to Evaluate Weight-based Enoxaparin Dosing in Obese Medical Patients at Risk for DVT
NCT00632840	PHASE4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00636142	PHASE4	COMPLETED	Effects of Infliximab on Insulin Sensitivity and Beta Cell Function in Insulin Resistant Human Obesity
NCT00675987	PHASE4	COMPLETED	A Randomized Clinical Trial To Study Losartan On Endothelial Dysfunction and Insulin Resistance In Obese Patients
NCT00694811	PHASE4	COMPLETED	Effects of Re-Feeding Duration on Weight Maintenance After Weight Loss With Very-Low-Energy Diets (VLEDs)
NCT00699413	PHASE4	TERMINATED	Supplements for Controlling Resistance to Insulin
NCT00729963	PHASE4	COMPLETED	Sibutramine Versus Continuous Positive Airway Pressure (CPAP)in Obstructive Sleep Apnea (OSA) Patients