ASIC2

Summary

ASIC2 (acid sensing ion channel subunit 2, HGNC:99) is a protein-coding gene on chromosome 17q11.2-q12, encoding Acid-sensing ion channel 2 (Q16515). Forms pH-gated trimeric sodium channels that act as postsynaptic excitatory sensors in the nervous system.

This gene encodes a member of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily. The members of this family are amiloride-sensitive sodium channels that contain intracellular N and C termini, 2 hydrophobic transmembrane regions, and a large extracellular loop, which has many cysteine residues with conserved spacing. The member encoded by this gene may play a role in neurotransmission. In addition, a heteromeric association between this member and acid-sensing (proton-gated) ion channel 3 has been observed to co-assemble into proton-gated channels sensitive to gadolinium. Alternative splicing has been observed at this locus and two variants, encoding distinct isoforms, have been identified.

Source: NCBI Gene 40 — RefSeq curated summary.

At a glance

• Gene–disease (curated): premature ovarian failure 16 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 27
• Clinical variants (ClinVar): 244 total — 3 pathogenic, 4 likely-pathogenic
• MANE Select transcript: NM_183377

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:99
Approved symbol	ASIC2
Name	acid sensing ion channel subunit 2
Location	17q11.2-q12
Locus type	gene with protein product
Status	Approved
Aliases	ASIC2a, BNC1, BNaC1, hBNaC1, MDEG
Ensembl gene	ENSG00000108684
Ensembl biotype	protein_coding
OMIM	601784
Entrez	40

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding_CDS_not_defined, 2 protein_coding

ENST00000225823, ENST00000359872, ENST00000448983, ENST00000579816, ENST00000583395

RefSeq mRNA: 2 — MANE Select: NM_183377 NM_001094, NM_183377

CCDS: CCDS11276, CCDS42296

Canonical transcript exons

ENST00000225823 — 10 exons

Exon	Start	End
ENSE00000713546	33015971	33016039
ENSE00000713550	33017605	33017684
ENSE00000713553	33021219	33021310
ENSE00000713555	33023861	33024014
ENSE00001248819	33013087	33014066
ENSE00001248823	33291408	33293295
ENSE00003603257	33111917	33112067
ENSE00003642536	33088863	33088990
ENSE00003660282	33025926	33025982
ENSE00003665623	33028242	33028392

Expression profiles

Bgee: expression breadth ubiquitous, 131 present calls, max score 83.25.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5295 / max 19.7413, expressed in 181 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165268	0.2989	138
165281	0.1637	62
165267	0.0669	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	83.25	gold quality
cingulate cortex	UBERON:0003027	80.09	gold quality
anterior cingulate cortex	UBERON:0009835	79.89	gold quality
frontal cortex	UBERON:0001870	79.31	gold quality
Brodmann (1909) area 9	UBERON:0013540	78.74	gold quality
neocortex	UBERON:0001950	78.62	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	78.44	gold quality
cerebellar cortex	UBERON:0002129	77.15	gold quality
cerebellar hemisphere	UBERON:0002245	77.14	gold quality
right hemisphere of cerebellum	UBERON:0014890	76.97	gold quality
Brodmann (1909) area 10	UBERON:0013541	76.96	silver quality
Brodmann (1909) area 46	UBERON:0006483	76.89	gold quality
orbitofrontal cortex	UBERON:0004167	76.77	silver quality
cerebral cortex	UBERON:0000956	76.75	gold quality
hypothalamus	UBERON:0001898	76.57	gold quality
right frontal lobe	UBERON:0002810	76.57	gold quality
cerebellum	UBERON:0002037	75.76	gold quality
amygdala	UBERON:0001876	75.70	gold quality
CA1 field of hippocampus	UBERON:0003881	74.91	silver quality
telencephalon	UBERON:0001893	74.09	gold quality
superior frontal gyrus	UBERON:0002661	73.62	gold quality
Ammon’s horn	UBERON:0001954	73.52	gold quality
postcentral gyrus	UBERON:0002581	72.98	gold quality
cortical plate	UBERON:0005343	72.82	gold quality
temporal lobe	UBERON:0001871	72.52	gold quality
nucleus accumbens	UBERON:0001882	72.27	gold quality
brain	UBERON:0000955	71.56	gold quality
forebrain	UBERON:0001890	71.55	gold quality
central nervous system	UBERON:0001017	71.27	gold quality
parietal lobe	UBERON:0001872	70.87	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	5559.50
E-HCAD-30	yes	5049.81
E-HCAD-25	yes	4421.36
E-ANND-3	no	2.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

82 targeting ASIC2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-12122	99.56	69.33	1672

Literature-anchored findings (GeneRIF, showing 24)

• the ASIC2a subtype consists of intracellular amino and carboxyl termini and two transmembrane domains connected by a large extracellular loop (PMID:15504740)
• ASIC2 surface expression inhibits the amiloride-sensitive current and migration of glioma cells (PMID:16704974)
• Application of these methods allowed us to find a significant association between MS and the SNP rs28936 located in the 3’ UTR segment of ACCN1 with p = 0.0004 (p = 0.002, after adjusting for multiple testing) (PMID:17534430)
• AKAP150 and the protein phosphatase calcineurin are binding proteins to ASIC2a, and calcineurin regulates ASIC1a and ASIC2a activity (PMID:17548344)
• This work provides a mechanism explaining how defects in parkin-mediated PICK1 monoubiquitination could enhance ASIC activity and thereby promote neurodegeneration in Parkinson’s disease. (PMID:17553932)
• Two PKC consensus sites on human acid-sensing ion channel 1b differentially regulate its function. (PMID:19091960)
• These results demonstrate for the first time the differential distribution of ASIC1 and ASIC2 in human rapidly adapting low-threshold mechanoreceptors, and suggest specific roles of both proteins in mechanotransduction. (PMID:20306292)
• ACCN1 might be one of numerous susceptibility genes for panic disorder. (PMID:21811305)
• these results indicate that ACCN1 gene is a potential candidate for response to lithium treatment that would serve as a genetic marker of lithium efficacy for bipolar disorder patients. (PMID:21961650)
• The results showed that there was a significant increase in the mean relative optical density of ASIC2 and ASIC3 but not ASIC1a in the lining epithelium and glandular tubes of gastric mucosa in patients with Henoch-Schonlein purpura. (PMID:22157923)
• Combinatorial analysis suggests a model of random mixing of ASIC1a and ASIC2a subunits to yield both 2:1 and 1:2 ASIC1a:ASIC2a heteromers together with ASIC1a and ASIC2a homomers. (PMID:24847067)
• distribution of ASIC2 in the human cutaneous mechanosensory system and suggest the involvement of ASIC2 in mechanosensation (PMID:25224144)
• ASICs may enhance susceptibility to epileptogenesis in the piriform cortex. (PMID:25744567)
• This study suggests that ASIC2 may play a role as mediators of inflammatory pain and be involved in the pathogenesis of frozen shoulder. (PMID:26033064)
• results demonstrate the occurrence of ASIC2 and TrkB in the human intervertebral disc (IVD), and the increased expression of both in pathological IVD suggest their involvement in IVD degeneration (PMID:26617738)
• The ASIC2 are involved in fear behaviours, learning and memory functions, and pain sensation. (PMID:27278329)
• The authors finally confirmed that the ASIC2b isoform is delivered to the cell surface from the endoplasmic reticulum by forming heteromers with ASIC2a isoform, and that the N-terminal region of ASIC2a is additionally required for the ASIC2a-dependent membrane targeting of ASIC2b. (PMID:27477936)
• The results show that acid-sensing ion channel 1, acid-sensing ion channel 2, and acid-sensing ion channel 3 are expressed in A549 cells at the messenger RNA and protein levels, and acid-sensing ion channel-like currents were elicited by extracellular acid stimuli. (PMID:28618956)
• hippocampal glucose hypometabolism elevates ASIC2a expression by suppressing TFCP2 expression, which further enhances the intrinsic excitability of CA1 pyramidal neurons and increases seizure susceptibility in patients with temporal lobe epilepsy. (PMID:28725010)
• Study shows that ASIC2 promotes metastasis of colorectal cancer (CRC) cells by activating the calcineurin/NFAT1 pathway under acidosis and high expression of ASIC2 predicts poor outcomes of patients with CRC. (PMID:28927426)
• Analysis of human autoptic brain tissue in multiple sclerosis (MS) and control samples showed an increase of ASIC 2 mRNA in MS samples. (PMID:30549327)
• ASIC2 could be crucial in the pathogenesis of osteoporosis and could serve as a therapeutic target for antiosteoporotic therapies. (PMID:31531354)
• Expression Profiles of ASIC1/2 and TRPV1/4 in Common Skin Tumors. (PMID:34199609)
• ASIC2 Synergizes with TRPV1 in the Mechano-Electrical Transduction of Arterial Baroreceptors. (PMID:34215968)

Cross-species orthologs

27 orthologs

Organism	Symbol	Gene ID
danio_rerio	asic2	ENSDARG00000006849
mus_musculus	Asic2	ENSMUSG00000020704
rattus_norvegicus	Asic2	ENSRNOG00000058308
drosophila_melanogaster	Nach	FBGN0024319
drosophila_melanogaster	ppk28	FBGN0030795
drosophila_melanogaster	ppk17	FBGN0032602
drosophila_melanogaster	ppk6	FBGN0034489
drosophila_melanogaster	ppk12	FBGN0034730
drosophila_melanogaster	ppk29	FBGN0034965
drosophila_melanogaster	ppk24	FBGN0039839
drosophila_melanogaster	ppk22	FBGN0051105
drosophila_melanogaster	ppk8	FBGN0052792
drosophila_melanogaster	ppk5	FBGN0053289
drosophila_melanogaster	ppk16	FBGN0065108
drosophila_melanogaster	ppk11	FBGN0065109
drosophila_melanogaster	ppk9	FBGN0085398
drosophila_melanogaster	ppk18	FBGN0265001
caenorhabditis_elegans		WBGENE00003168
caenorhabditis_elegans		WBGENE00003174
caenorhabditis_elegans		WBGENE00007518
caenorhabditis_elegans		WBGENE00009073
caenorhabditis_elegans		WBGENE00011891
caenorhabditis_elegans	delm-2	WBGENE00016063
caenorhabditis_elegans	acd-1	WBGENE00016064
caenorhabditis_elegans	acd-2	WBGENE00016066
caenorhabditis_elegans		WBGENE00016699
caenorhabditis_elegans		WBGENE00017879

Paralogs (8): ASIC4 (ENSG00000072182), ASIC1 (ENSG00000110881), SCNN1A (ENSG00000111319), SCNN1D (ENSG00000162572), SCNN1G (ENSG00000166828), SCNN1B (ENSG00000168447), ASIC3 (ENSG00000213199), ASIC5 (ENSG00000256394)

Protein

Protein identifiers

Acid-sensing ion channel 2 — Q16515 (reviewed: Q16515)

Alternative names: Amiloride-sensitive cation channel 1, neuronal, Amiloride-sensitive cation channel neuronal 1, Brain sodium channel 1, Mammalian degenerin homolog

All UniProt accessions (1): Q16515

UniProt curated annotations — full annotation on UniProt →

Function. Forms pH-gated trimeric sodium channels that act as postsynaptic excitatory sensors in the nervous system. Upon extracellular acidification, these channels generate rapid, transient inward currents that fully desensitize. Highly selective for sodium, they are permeable to other cations. By forming heterotrimeric channels with ASIC1, could contribute to synaptic plasticity, learning, and memory. Additionally, as acid sensors at nerve terminals, plays a role in mechanosensation and phototransduction.

Subunit / interactions. Can form homotrimers. Heterotrimer; forms functional heterotrimers producing channel with different properties. Forms heterotrimers with ASIC1; while ASIC1 determines current amplitude, ASIC2 influences the properties of the current. Forms heterotrimers with ASIC3; resulting in channels with distinct properties. Interacts with STOM; STOM regulates the gating of ASIC2-containing channels. Interacts with PICK1; promotes ASIC3 phosphorylation by PKC and activation of ASIC2/ASIC3 heterotrimers.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in brain, cerebellum, trigeminal sensory ganglia and also detected in testis.

Activity regulation. Inhibited by the diuretic drug amiloride. Inhibited by gadolinium ions, the heterotrimer with ASIC3 being more sensitive. Heterotrimer composed of ASIC1 and ASIC2 are inhibited by the snake venom mambalgin-1.

Similarity. Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. ASIC2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q16515-1	1, Asic2a, MDEG1	yes
Q16515-2	2, Asic2b, MDEG2

RefSeq proteins (2): NP_001085, NP_899233* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001873	ENaC	Family
IPR004724	ENaC_chordates	Family
IPR020903	ENaC_CS	Conserved_site

Pfam: PF00858

Catalyzed reactions (Rhea), 3 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Na(+)(in) = Na(+)(out) (RHEA:34963)
• Li(+)(in) = Li(+)(out) (RHEA:78551)

UniProt features (60 total): helix 17, strand 15, disulfide bond 6, turn 4, topological domain 3, glycosylation site 2, splice variant 2, transmembrane region 2, mutagenesis site 2, sequence conflict 2, modified residue 2, chain 1, sequence variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6L6P	X-RAY DIFFRACTION	3.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16515-F1	86.90	0.71

Functional residue map

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

Post-translational modifications (2): 8, 11

Disulfide bonds (6): 92–193, 289–364, 307–360, 311–358, 320–342, 322–334

Glycosylation sites (2): 392, 365

Mutagenesis-validated functional residues (2):

Position	Phenotype
430	no effect on cation channel activity.
430	increased cation channel activity; constitutively active.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-382551	Transport of small molecules
R-HSA-983712	Ion channel transport

MSigDB gene sets: 431 (showing top): GGGACCA_MIR133A_MIR133B, RNGTGGGC_UNKNOWN, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_REGULATION_OF_CELL_MATURATION, FREAC2_01, BENPORATH_ES_WITH_H3K27ME3, MODULE_274, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SYNAPSE_ASSEMBLY, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION, LFA1_Q6, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GCANCTGNY_MYOD_Q6

GO Biological Process (23): regulation of systemic arterial blood pressure by aortic arch baroreceptor feedback (GO:0003026), synapse assembly (GO:0007416), phototransduction (GO:0007602), sensory perception of sound (GO:0007605), regulation of vasoconstriction (GO:0019229), regulation of monoatomic ion transmembrane transport (GO:0034765), protein localization to synapse (GO:0035418), sodium ion transmembrane transport (GO:0035725), regulation of membrane potential (GO:0042391), negative regulation of apoptotic process (GO:0043066), sensory perception of sour taste (GO:0050915), detection of mechanical stimulus involved in sensory perception (GO:0050974), establishment of localization in cell (GO:0051649), positive regulation of synapse assembly (GO:0051965), cellular response to xenobiotic stimulus (GO:0071466), cellular response to acidic pH (GO:0071468), regulation of postsynapse assembly (GO:0150052), monoatomic ion transport (GO:0006811), monoatomic cation transport (GO:0006812), sodium ion transport (GO:0006814), response to mechanical stimulus (GO:0009612), response to acidic pH (GO:0010447), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (7): ligand-gated sodium channel activity (GO:0015280), monoatomic ion-gated channel activity (GO:0022839), pH-gated sodium channel activity (GO:0160125), monoatomic ion channel activity (GO:0005216), monoatomic cation channel activity (GO:0005261), sodium channel activity (GO:0005272), protein binding (GO:0005515)

GO Cellular Component (7): plasma membrane (GO:0005886), neuronal cell body (GO:0043025), dendritic spine (GO:0043197), postsynaptic density membrane (GO:0098839), membrane (GO:0016020), neuron projection (GO:0043005), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sensory perception of mechanical stimulus	2
monoatomic ion transmembrane transport	2
regulation of synapse assembly	2
nervous system process involved in regulation of systemic arterial blood pressure	1
regulation of systemic arterial blood pressure by baroreceptor feedback	1
nervous system development	1
cell junction assembly	1
synapse organization	1
signal transduction	1
detection of light stimulus	1
vasoconstriction	1
blood vessel diameter maintenance	1
regulation of blood circulation	1
regulation of transmembrane transport	1
regulation of monoatomic ion transport	1
protein localization to cell junction	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
regulation of biological quality	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
sensory perception of taste	1
sensory perception	1
detection of stimulus involved in sensory perception	1
detection of mechanical stimulus	1
establishment of localization	1
cellular localization	1
synapse assembly	1
positive regulation of nervous system development	1
positive regulation of cell junction assembly	1
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
response to acidic pH	1
cellular response to pH	1
postsynapse assembly	1
regulation of postsynapse organization	1
transport	1
monoatomic ion transport	1
metal ion transport	1

Protein interactions and networks

STRING

1468 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASIC2	ASIC1	P78348	907
ASIC2	PICK1	Q9NRD5	812
ASIC2	DLG4	P78352	722
ASIC2	ASIC4	Q96FT7	699
ASIC2	STOM	P27105	695
ASIC2	TRPV1	Q8NER1	679
ASIC2	TRPA1	O75762	613
ASIC2	PIEZO2	Q9H5I5	601
ASIC2	TRPV4	Q9HBA0	592
ASIC2	SCNN1G	P51170	580
ASIC2	SCNN1B	P51168	578
ASIC2	SCNN1A	P37088	577
ASIC2	PRSS8	Q16651	564
ASIC2	LIN7B	Q9HAP6	560
ASIC2	P2RX4	Q99571	554

IntAct

8 interactions, top by confidence:

A	B	Type	Score
ASIC2	PICK1	psi-mi:“MI:0915”(physical association)	0.510
PICK1	ASIC2	psi-mi:“MI:0915”(physical association)	0.510
ASIC2	Pick1	psi-mi:“MI:0915”(physical association)	0.400
ASIC1	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
ASIC2	PLD2	psi-mi:“MI:0914”(association)	0.350
ASIC2	ASIC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (17): ASIC2 (Affinity Capture-Western), ASIC2 (Affinity Capture-MS), ASIC3 (Affinity Capture-Western), ASIC2 (Affinity Capture-MS), PLD2 (Affinity Capture-MS), PLD1 (Affinity Capture-MS), FAR2 (Affinity Capture-MS), HADHB (Affinity Capture-MS), ASIC2 (Affinity Capture-MS), IQGAP2 (Affinity Capture-MS), SEC62 (Affinity Capture-MS), Pick1 (Affinity Capture-Western), ERMP1 (Affinity Capture-MS), YME1L1 (Affinity Capture-MS), HS2ST1 (Affinity Capture-MS)

ESM2 similar proteins: A2AIR5, A2RRU4, A4Q9F4, A6QM06, C0HL12, D4A6L0, E1BBQ2, H2Q5A1, K7GET2, O14514, O46547, O75077, O97741, P37088, P37089, P55270, P55926, P56726, P97260, Q12770, Q13563, Q16515, Q3UHD1, Q5E9P6, Q5MNU5, Q60HE8, Q61180, Q62962, Q6GQT6, Q6NXK8, Q708S5, Q7TNS7, Q7TSQ1, Q80UW0, Q8BQ86, Q8NHH1, Q8TCU5, Q92075, Q924S4, Q925H0

Diamond homologs: O35240, P55926, P78348, Q10025, Q16515, Q1XA76, Q62962, Q6NXK8, Q6X1Y6, Q708S3, Q708S4, Q708S5, Q708S6, Q708S7, Q708S8, Q7T1N4, Q7TNS7, Q925H0, Q96FT7, Q9JHS6, Q9NY37, Q9R0W5, Q9R0Y1, Q9UHC3, Q25011, H1AFJ5, H2Q5A1, H9GBX2, K7GET2, O13263, O97741, P24585, P24612, P34886, P37088, P37089, P51169, P51171, P51172, Q09274

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	4
Uncertain significance	213
Likely benign	11
Benign	5

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
3770194	NM_001094.5(ASIC2):c.556-198516_556-198515insTTACCTGCAATGTGCTGGGTTATCTGTTCCTTCTCATTATCTTCCAGCTCTTCCCAGCCTTCCAGCTCTGTGAGGTCCTCGATYTTGTT	Pathogenic
443455	GRCh37/hg19 17q11.2-12(chr17:29578241-32142196)x1	Pathogenic
800707	NM_001717.4(BNC1):c.1065_1069del (p.Arg356fs)	Pathogenic
2690982	NM_001717.4(BNC1):c.621_637del (p.Phe207fs)	Likely pathogenic
2690983	NM_001717.4(BNC1):c.1874_1875del (p.Pro625fs)	Likely pathogenic
3600994	NM_001094.5(ASIC2):c.556-384796G>A	Likely pathogenic
929778	NM_001717.4(BNC1):c.2273C>T (p.Thr758Ile)	Likely pathogenic

SpliceAI

4331 predictions. Top by Δscore:

Variant	Effect	Δscore
17:33014065:CT:C	acceptor_gain	1.0000
17:33015965:TCTTA:T	donor_loss	1.0000
17:33015966:CTTA:C	donor_loss	1.0000
17:33015968:TA:T	donor_loss	1.0000
17:33015970:CCA:C	donor_gain	1.0000
17:33016036:TCAG:T	acceptor_gain	1.0000
17:33016037:CAG:C	acceptor_gain	1.0000
17:33016037:CAGC:C	acceptor_gain	1.0000
17:33016038:AG:A	acceptor_gain	1.0000
17:33016038:AGC:A	acceptor_loss	1.0000
17:33016039:GCTG:G	acceptor_loss	1.0000
17:33016040:C:CC	acceptor_gain	1.0000
17:33016041:T:A	acceptor_loss	1.0000
17:33016043:C:CT	acceptor_gain	1.0000
17:33016044:A:T	acceptor_gain	1.0000
17:33021215:TTAC:T	donor_loss	1.0000
17:33021216:TACCA:T	donor_loss	1.0000
17:33021217:A:AC	donor_gain	1.0000
17:33021217:A:T	donor_loss	1.0000
17:33021217:AC:A	donor_gain	1.0000
17:33021218:C:CT	donor_gain	1.0000
17:33021218:CC:C	donor_gain	1.0000
17:33021218:CCA:C	donor_gain	1.0000
17:33021307:CTCT:C	acceptor_gain	1.0000
17:33021308:TCT:T	acceptor_gain	1.0000
17:33021309:CTC:C	acceptor_gain	1.0000
17:33021310:TCT:T	acceptor_gain	1.0000
17:33021311:C:A	acceptor_loss	1.0000
17:33021311:C:CC	acceptor_gain	1.0000
17:33021312:T:C	acceptor_loss	1.0000

AlphaMissense

3667 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:33017636:G:A	T446I	1.000
17:33017639:A:T	L445H	1.000
17:33017644:A:C	S443R	1.000
17:33017644:A:T	S443R	1.000
17:33017645:C:A	S443I	1.000
17:33017646:T:G	S443R	1.000
17:33017651:C:A	G441V	1.000
17:33017651:C:T	G441D	1.000
17:33017652:C:G	G441R	1.000
17:33017660:A:G	L438S	1.000
17:33017663:C:T	G437E	1.000
17:33017664:C:G	G437R	1.000
17:33017664:C:T	G437R	1.000
17:33017675:C:A	G433V	1.000
17:33017675:C:T	G433D	1.000
17:33017676:C:G	G433R	1.000
17:33021293:A:G	L405P	1.000
17:33021299:A:G	L403P	1.000
17:33023937:A:G	S374P	1.000
17:33025943:C:G	C342S	1.000
17:33025944:A:T	C342S	1.000
17:33025966:A:C	C334W	1.000
17:33025967:C:G	C334S	1.000
17:33025967:C:T	C334Y	1.000
17:33025968:A:G	C334R	1.000
17:33025968:A:T	C334S	1.000
17:33028262:C:G	C322S	1.000
17:33028263:A:G	C322R	1.000
17:33028263:A:T	C322S	1.000
17:33028267:G:C	C320W	1.000

dbSNP variants (sampled 300 via entrez): RS1000003227 (17:33674060 A>C), RS1000011179 (17:33987955 T>C), RS1000011904 (17:33714642 G>A,T), RS1000012356 (17:34033613 T>C), RS1000015391 (17:33639961 T>C), RS1000017219 (17:33574164 A>G), RS1000017336 (17:33364914 C>A), RS1000018406 (17:33550929 G>C), RS1000019927 (17:33870539 C>T), RS1000021206 (17:33756517 C>G), RS1000021253 (17:33544218 T>C), RS1000023787 (17:33418882 C>T), RS1000024636 (17:33238706 A>G), RS1000027663 (17:33238790 G>A), RS1000027721 (17:33675752 C>T)

Disease associations

OMIM: gene MIM:601784 | disease phenotypes: MIM:618723, MIM:115200, MIM:619780, MIM:233300

GenCC curated gene-disease

Disease	Classification	Inheritance
premature ovarian failure 16	Strong	Autosomal dominant
46 XX gonadal dysgenesis	Supportive	Autosomal dominant

Mondo (7): premature ovarian failure 16 (MONDO:0032881), prostate cancer (MONDO:0008315), dilated cardiomyopathy 1A (MONDO:0007269), mitochondrial DNA depletion syndrome 20 (mngie type) (MONDO:0030696), 46 XX gonadal dysgenesis (MONDO:0009299), neurodevelopmental disorder (MONDO:0700092), primary ovarian failure (MONDO:0005387)

Orphanet (5): Familial prostate cancer (Orphanet:1331), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), Familial dilated cardiomyopathy with conduction defect due to LMNA mutation (Orphanet:300751), 46,XX gonadal dysgenesis (Orphanet:243), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST001188_3	vWF and FVIII levels	2.000000e-06
GCST001762_13	Obesity-related traits	4.000000e-06
GCST002279_41	PR interval in Tripanosoma cruzi seropositivity	1.000000e-07
GCST002337_161	Amyotrophic lateral sclerosis (sporadic)	4.000000e-06
GCST003264_897	Post bronchodilator FEV1/FVC ratio	5.000000e-06
GCST003425_9	Longevity	6.000000e-06
GCST004029_25	Angiotensin-converting enzyme inhibitor intolerance	7.000000e-07
GCST004198_5	Severe gingival inflammation	4.000000e-08
GCST004264_7	Clopidogrel active metabolite levels	1.000000e-08
GCST004863_83	Mosquito bite size	5.000000e-06
GCST006137_11	Serum folate levels	3.000000e-06
GCST006431_5	Plasma parathyroid hormone levels	2.000000e-06
GCST006659_2	Polycystic ovary syndrome	8.000000e-06
GCST006988_93	Blond vs. brown/black hair color	1.000000e-14
GCST007018_5	Serum bilirubin levels in metabolic syndrome	1.000000e-06
GCST007576_219	Chronotype	3.000000e-08
GCST007576_407	Chronotype	3.000000e-08
GCST008802_2	Smoking behaviour (age at first cigarette)	1.000000e-08
GCST009203_13	Cerebellum cortex volume	2.000000e-06
GCST009823_6	Gynecologic disease (multivariate analysis)	3.000000e-08
GCST010397_70	Gut microbiota (bacterial taxa, rank normal transformation method)	5.000000e-06
GCST010988_59	Adult body size	2.000000e-08
GCST011536_5	Intestinal permeability measurement	8.000000e-06
GCST011703_21	Smoking initiation	6.000000e-11
GCST011985_1	Congenital heart disease (septal defects)	7.000000e-08
GCST012490_486	Femur bone mineral density x serum urate levels interaction	1.000000e-09
GCST012498_11	Autism	3.000000e-06

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004630	factor VIII measurement
EFO:0004462	PR interval
EFO:0004713	FEV/FVC ratio
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0007966	clopidogrel metabolite measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0003924	hair color
EFO:0004570	bilirubin measurement
EFO:0008328	chronotype measurement
EFO:0005670	smoking initiation
EFO:0007874	gut microbiome measurement
EFO:0011031	intestinal permeability measurement
EFO:0004531	urate measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D023961	Gonadal Dysgenesis, 46,XX	C12.050.351.875.253.064.249; C12.050.351.875.253.309.193; C12.200.706.316.064.249; C12.200.706.316.309.193; C12.800.316.064.249; C12.800.316.309.193; C16.131.939.316.064.249; C16.131.939.316.309.193; C19.391.119.064.249; C19.391.119.309.193
D065886	Neurodevelopmental Disorders	F03.625
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11869731	Efficacy	3	lithium	Bipolar Disorder

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11869731	ASIC2	3	3.00	1	lithium

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: lgic — Acid-sensing (proton-gated) ion channels (ASICs)

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
diminazene	Channel blocker	6.1	pIC50
H+	Activator	5.0	pEC50
amiloride	Channel blocker	4.6	pIC50
A-317567	Channel blocker	4.5	pIC50
nafamostat	Channel blocker	4.2	pIC50
Cd2+	Channel blocker	3.0	pIC50

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases methylation	2
bisphenol A	affects methylation, increases methylation, affects cotreatment	1
arsenite	increases methylation	1
sodium arsenite	increases expression	1
benzo(e)pyrene	increases methylation	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Arsenic	affects methylation	1
Copper	affects cotreatment, decreases expression	1
Folic Acid	decreases expression	1
Methapyrilene	increases methylation	1
Methotrexate	increases expression	1
Silicon Dioxide	increases expression	1
Tretinoin	increases expression	1
Triclosan	decreases expression	1
Sodium Selenite	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer