TMC2

Summary

TMC2 (transmembrane channel like 2, HGNC:16527) is a protein-coding gene on chromosome 20p13, encoding Transmembrane channel-like protein 2 (Q8TDI7). Pore-forming subunit of the mechanotransducer (MET) non-selective cation channel complex located at the tips of stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system.

This gene encodes a transmembrane protein that is necesssary for mechanotransduction in cochlear hair cells of the inner ear. Mutations in this gene may underlie hereditary disorders of balance and hearing.

Source: NCBI Gene 117532 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 186 total
• MANE Select transcript: NM_080751

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16527
Approved symbol	TMC2
Name	transmembrane channel like 2
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	dJ686C3.3
Ensembl gene	ENSG00000149488
Ensembl biotype	protein_coding
OMIM	606707
Entrez	117532

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 1 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000358864, ENST00000496948, ENST00000644205

RefSeq mRNA: 1 — MANE Select: NM_080751 NM_080751

CCDS: CCDS13029

Canonical transcript exons

ENST00000358864 — 20 exons

Exon	Start	End
ENSE00000990605	2617072	2617311
ENSE00000990606	2624271	2624396
ENSE00000990607	2635926	2636004
ENSE00001164520	2641134	2643580
ENSE00001164526	2637474	2637591
ENSE00001592264	2558456	2558774
ENSE00001601585	2572179	2572269
ENSE00001619447	2597151	2597298
ENSE00001630311	2602113	2602301
ENSE00001653167	2613194	2613322
ENSE00001657441	2594825	2594967
ENSE00001677368	2579146	2579227
ENSE00001708962	2561858	2562010
ENSE00001753325	2592310	2592408
ENSE00001764342	2579950	2580056
ENSE00001770727	2537269	2537316
ENSE00002242638	2536573	2536655
ENSE00003572708	2612191	2612340
ENSE00003583470	2616137	2616204
ENSE00003619163	2610419	2610598

Expression profiles

Bgee: expression breadth ubiquitous, 121 present calls, max score 86.38.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0219 / max 13.4512, expressed in 7 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183168	0.0129	4
183169	0.0091	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	86.38	gold quality
cerebellar cortex	UBERON:0002129	86.19	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.13	gold quality
cerebellum	UBERON:0002037	82.99	gold quality
cortical plate	UBERON:0005343	74.01	gold quality
adenohypophysis	UBERON:0002196	71.41	gold quality
pituitary gland	UBERON:0000007	71.06	gold quality
hypothalamus	UBERON:0001898	62.12	gold quality
nucleus accumbens	UBERON:0001882	61.08	gold quality
ganglionic eminence	UBERON:0004023	60.05	gold quality
upper leg skin	UBERON:0004262	60.03	silver quality
brain	UBERON:0000955	58.33	gold quality
decidua	UBERON:0002450	57.12	gold quality
right lung	UBERON:0002167	57.02	gold quality
postcentral gyrus	UBERON:0002581	56.81	gold quality
amygdala	UBERON:0001876	56.38	gold quality
right frontal lobe	UBERON:0002810	55.94	gold quality
forebrain	UBERON:0001890	55.61	gold quality
caudate nucleus	UBERON:0001873	55.41	gold quality
anterior cingulate cortex	UBERON:0009835	55.29	gold quality
subcutaneous adipose tissue	UBERON:0002190	54.99	gold quality
Ammon’s horn	UBERON:0001954	54.38	gold quality
Brodmann (1909) area 9	UBERON:0013540	54.34	gold quality
colonic epithelium	UBERON:0000397	54.32	gold quality
parietal lobe	UBERON:0001872	54.31	gold quality
putamen	UBERON:0001874	53.93	gold quality
superior frontal gyrus	UBERON:0002661	53.83	silver quality
mammary duct	UBERON:0001765	53.68	gold quality
neocortex	UBERON:0001950	53.56	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	53.51	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	5.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

22 targeting TMC2, 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-1252-5P	100.00	69.80	2774
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-589-5P	98.72	66.96	927
HSA-MIR-7155-5P	98.65	66.14	1290
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-6793-3P	97.66	65.78	1084
HSA-MIR-6839-5P	96.74	68.29	1088
HSA-MIR-378J	96.44	66.20	1020
HSA-MIR-6813-3P	95.78	63.78	540
HSA-MIR-6851-3P	95.73	65.11	688
HSA-MIR-2861	95.24	65.47	1056

Literature-anchored findings (GeneRIF, showing 2)

• Autozygosity by descent analysis of 2 markers bordering the TMC2 gene allowed us to rule out its association with deafness within these families. (PMID:18259073)
• But the great majority of evidence is consistent with these TMCs as pore-forming subunits of the long-sought hair-cell transduction channel. [review] (PMID:27798174)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmc2b	ENSDARG00000030311
danio_rerio	tmc2a	ENSDARG00000033104
mus_musculus	Tmc2	ENSMUSG00000060332
rattus_norvegicus	Tmc2	ENSRNOG00000007017
drosophila_melanogaster	Tmc	FBGN0267796

Paralogs (7): TMC5 (ENSG00000103534), TMC6 (ENSG00000141524), TMC1 (ENSG00000165091), TMC4 (ENSG00000167608), TMC8 (ENSG00000167895), TMC7 (ENSG00000170537), TMC3 (ENSG00000188869)

Protein

Protein identifiers

Transmembrane channel-like protein 2 — Q8TDI7 (reviewed: Q8TDI7)

Alternative names: Transmembrane cochlear-expressed protein 2

All UniProt accessions (2): Q8TDI7, A0A2R8YFP4

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of the mechanotransducer (MET) non-selective cation channel complex located at the tips of stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system. The MET complex is composed of two dimeric pore-forming ion-conducting transmembrane TMC (TMC1 or TMC2) subunits, and aided by several auxiliary proteins including LHFPL5, TMIE, CIB2/3 and TOMT, and the tip-link PCDH15. MET channel is activated by tension in the tip-link extending from the side wall of one stereocilium to the tip of the adjacent shorter stereocilium, where the channel is located. TMC2 MET channel is highly permeable to calcium and likely transports monovalent cations. Also involved in vestibular hair cell transduction current of the mammalian inner ear.

Subunit / interactions. Forms the MET channel composed of TMC dimer (TMC1 or TMC2), TMIE, TOMT, CIB (CIB2 or CIB3), LHFPL5 and PDH15. The interaction of TMC1 and TMC2 with TOMT is required for the transportation of TMC1/2 into the stereocilia of hair cells. Interacts (via N-terminus) with both isoforms CD1 and CD3 of PCDH15. Can form a heterodimer with TMC1, TMC5 or TMC7.

Subcellular location. Cell membrane.

Tissue specificity. Detected in fetal cochlea.

Similarity. Belongs to the TMC family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TDI7-1	1	yes
Q8TDI7-3	2
Q8TDI7-4	3

RefSeq proteins (1): NP_542789* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012496	TMC_dom	Domain
IPR038900	TMC	Family

Pfam: PF07810

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)

UniProt features (34 total): topological domain 7, sequence variant 7, transmembrane region 6, compositionally biased region 6, splice variant 5, region of interest 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDI7-F1	68.07	0.07

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea

MSigDB gene sets: 71 (showing top): GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION, GOBP_REFLEX, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_DETECTION_OF_MECHANICAL_STIMULUS, GOBP_REGULATION_OF_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION_OF_SOUND, GOBP_DETECTION_OF_ABIOTIC_STIMULUS, GOBP_DETECTION_OF_STIMULUS, GOBP_SENSORY_PERCEPTION, GOCC_NEURON_PROJECTION, GOBP_REGULATION_OF_TRANSPORT, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_MONOATOMIC_ION_TRANSPORT

GO Biological Process (6): detection of mechanical stimulus involved in sensory perception of sound (GO:0050910), vestibular reflex (GO:0060005), regulation of calcium ion transmembrane transport (GO:1903169), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (3): voltage-gated calcium channel activity (GO:0005245), calcium channel activity (GO:0005262), mechanosensitive monoatomic ion channel activity (GO:0008381)

GO Cellular Component (5): plasma membrane (GO:0005886), stereocilium (GO:0032420), stereocilium tip (GO:0032426), cuticular plate (GO:0032437), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sensory processing of sound	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
sensory perception of sound	1
nervous system process	1
detection of mechanical stimulus involved in sensory perception	1
reflex	1
regulation of calcium ion transport	1
calcium ion transmembrane transport	1
regulation of monoatomic cation transmembrane transport	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
calcium channel activity	1
voltage-gated monoatomic cation channel activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
monoatomic ion channel activity	1
gated channel activity	1
membrane	1
cell periphery	1
stereocilium bundle	1
neuron projection	1
actin-based cell projection	1
stereocilium	1
cortical actin cytoskeleton	1

Protein interactions and networks

STRING

1238 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMC2	LHFPL5	Q8TAF8	981
TMC2	CIB2	O75838	905
TMC2	TMC1	Q8TDI8	890
TMC2	CDH23	Q9H251	870
TMC2	PCDH15	Q96QU1	869
TMC2	TMIE	Q8NEW7	864
TMC2	MYO7A	P78427	758
TMC2	E9PNW1	E9PNW1	738
TMC2	PIEZO1	Q92508	726
TMC2	STT3A	P46977	717
TMC2	WHRN	Q9P202	707
TMC2	PIEZO2	Q9H5I5	681
TMC2	CIB3	Q96Q77	607
TMC2	USH1G	Q495M9	606
TMC2	CIB4	A0PJX0	578

IntAct

2 interactions, top by confidence:

A	B	Type	Score
BMI1	MEIS3P1	psi-mi:“MI:0914”(association)	0.350

BioGRID (2): TMC2 (Affinity Capture-MS), TMC2 (Affinity Capture-MS)

ESM2 similar proteins: A0JPH4, A2AHL1, A8DZH4, D3ZWZ9, E7FFT2, F1QFU0, F1QZE9, P48763, P50482, P86044, Q28CV2, Q32NZ6, Q3TPR7, Q3ZAS0, Q4R7U0, Q4V8U5, Q5F3F5, Q5M7W4, Q5RH73, Q5YCC5, Q5ZKN3, Q68DH5, Q6GQE1, Q6P4P2, Q6UXY8, Q7L1W4, Q7Z2W7, Q7Z402, Q7ZYA0, Q810F5, Q8BH79, Q8C428, Q8C561, Q8CB19, Q8IZK6, Q8N3S3, Q8R455, Q8R4D5, Q8R4P4, Q8R4P5

Diamond homologs: A0A0U1QT59, E7FFT2, F1QFU0, F1QZE9, Q32NZ6, Q496Z4, Q4R7U0, Q5M7W4, Q6UXY8, Q7TN58, Q7TQ65, Q7Z402, Q7Z404, Q8C428, Q8IU68, Q8R4P4, Q8R4P5, Q8TDI7, Q8TDI8, D3KZG3, Q11069, Q5YCC7, Q7TQ69, Q7Z5M5, Q7TN60, Q7Z403

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
PCDH15	“up-regulates activity”	TMC2	binding
TMC2	“form complex”	“Hair cells mechanotransduction channel”	binding
CIB2	“up-regulates activity”	TMC2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	140
Likely benign	11
Benign	24

Top pathogenic / likely-pathogenic (0)

SpliceAI

4074 predictions. Top by Δscore:

Variant	Effect	Δscore
20:2562008:CAG:C	donor_loss	1.0000
20:2562012:T:A	donor_loss	1.0000
20:2579228:G:GG	donor_gain	1.0000
20:2579945:TCTAG:T	acceptor_loss	1.0000
20:2579946:CTA:C	acceptor_loss	1.0000
20:2579948:A:T	acceptor_loss	1.0000
20:2579949:G:GT	acceptor_loss	1.0000
20:2580054:GAG:G	donor_gain	1.0000
20:2610462:T:TA	acceptor_gain	1.0000
20:2613318:GATTT:G	donor_gain	1.0000
20:2613323:G:GG	donor_gain	1.0000
20:2613357:G:GT	donor_gain	1.0000
20:2613358:A:T	donor_gain	1.0000
20:2624269:AGT:A	acceptor_gain	1.0000
20:2624270:GT:G	acceptor_gain	1.0000
20:2624270:GTG:G	acceptor_gain	1.0000
20:2561843:T:TA	acceptor_gain	0.9900
20:2572174:A:G	acceptor_gain	0.9900
20:2578059:GTTT:G	donor_gain	0.9900
20:2579145:GAAAT:G	acceptor_gain	0.9900
20:2579224:GAAA:G	donor_gain	0.9900
20:2579225:AAAGT:A	donor_loss	0.9900
20:2579226:AAG:A	donor_loss	0.9900
20:2579227:AG:A	donor_loss	0.9900
20:2579228:GTGA:G	donor_loss	0.9900
20:2579229:T:G	donor_loss	0.9900
20:2579230:G:GT	donor_loss	0.9900
20:2579231:AGTA:A	donor_loss	0.9900
20:2579948:A:AG	acceptor_gain	0.9900
20:2579949:G:GG	acceptor_gain	0.9900

AlphaMissense

5968 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:2579200:T:A	W234R	1.000
20:2579200:T:C	W234R	1.000
20:2602218:A:C	S444R	1.000
20:2602220:T:A	S444R	1.000
20:2602220:T:G	S444R	1.000
20:2612322:G:C	W575C	1.000
20:2612322:G:T	W575C	1.000
20:2579202:G:C	W234C	0.999
20:2579202:G:T	W234C	0.999
20:2579955:T:C	F245L	0.999
20:2579957:T:A	F245L	0.999
20:2579957:T:G	F245L	0.999
20:2579959:G:T	G246V	0.999
20:2579979:T:C	F253L	0.999
20:2579981:C:A	F253L	0.999
20:2579981:C:G	F253L	0.999
20:2580011:C:A	N263K	0.999
20:2580011:C:G	N263K	0.999
20:2594825:G:C	G312R	0.999
20:2594945:A:C	S352R	0.999
20:2594947:C:A	S352R	0.999
20:2594947:C:G	S352R	0.999
20:2597230:T:A	W386R	0.999
20:2597230:T:C	W386R	0.999
20:2602228:T:C	L447P	0.999
20:2610555:T:C	L517P	0.999
20:2610576:T:C	L524P	0.999
20:2612317:T:C	C574R	0.999
20:2612318:G:A	C574Y	0.999
20:2612319:C:G	C574W	0.999

dbSNP variants (sampled 300 via entrez): RS1000014742 (20:2596127 G>A), RS1000032109 (20:2612964 G>T), RS1000036899 (20:2638734 GA>G,GAA), RS1000186865 (20:2577100 G>A), RS1000196614 (20:2588894 A>G), RS1000203928 (20:2632449 C>A), RS1000235197 (20:2548332 A>T), RS1000263717 (20:2612968 A>G), RS1000276496 (20:2638451 T>C), RS1000286091 (20:2536449 C>T), RS1000289477 (20:2619036 G>A), RS1000298109 (20:2625525 A>G,T), RS1000306252 (20:2638743 T>A), RS1000327466 (20:2625750 G>C), RS1000340752 (20:2541757 C>T)

Disease associations

OMIM: gene MIM:606707 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000996_7	Systemic lupus erythematosus	8.000000e-06
GCST001762_61	Obesity-related traits	2.000000e-06
GCST003139_20	Glomerular filtration rate in chronic kidney disease	2.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	increases methylation, decreases methylation	2
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	increases expression	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	increases expression	1
bisphenol S	decreases methylation	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Diazinon	increases methylation	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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