TMC8

Summary

TMC8 (transmembrane channel like 8, HGNC:20474) is a protein-coding gene on chromosome 17q25.3, encoding Transmembrane channel-like protein 8 (Q8IU68). Acts as a regulatory protein involved in the regulation of numerous cellular processes.

Epidermodysplasia verruciformis (EV) is an autosomal recessive dermatosis characterized by abnormal susceptibility to human papillomaviruses (HPVs) and a high rate of progression to squamous cell carcinoma on sun-exposed skin. EV is caused by mutations in either of two adjacent genes located on chromosome 17q25.3. Both of these genes encode integral membrane proteins that localize to the endoplasmic reticulum and are predicted to form transmembrane channels. This gene encodes a transmembrane channel-like protein with 8 predicted transmembrane domains and 3 leucine zipper motifs.

Source: NCBI Gene 147138 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epidermodysplasia verruciformis, susceptibility to, 2 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 15
• Clinical variants (ClinVar): 560 total — 22 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 15
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_152468

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20474
Approved symbol	TMC8
Name	transmembrane channel like 8
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	EVIN2
Ensembl gene	ENSG00000167895
Ensembl biotype	protein_coding
OMIM	605829
Entrez	147138

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 9 protein_coding_CDS_not_defined, 8 protein_coding, 5 retained_intron

ENST00000318430, ENST00000589691, ENST00000590184, ENST00000590426, ENST00000590799, ENST00000591003, ENST00000591144, ENST00000591983, ENST00000592399, ENST00000698566, ENST00000698567, ENST00000698568, ENST00000698569, ENST00000698570, ENST00000698571, ENST00000698572, ENST00000893785, ENST00000893786, ENST00000893787, ENST00000893788, ENST00000972441, ENST00000972442

RefSeq mRNA: 1 — MANE Select: NM_152468 NM_152468

CCDS: CCDS32749

Canonical transcript exons

ENST00000318430 — 16 exons

Exon	Start	End
ENSE00001118143	78131882	78132030
ENSE00001278031	78137235	78137358
ENSE00001278040	78134394	78134564
ENSE00001278533	78131281	78131737
ENSE00002276073	78138349	78138479
ENSE00002287490	78138574	78138732
ENSE00002293066	78138005	78138188
ENSE00002301239	78140834	78142968
ENSE00002361863	78134870	78135009
ENSE00002896298	78130771	78130851
ENSE00003474299	78139162	78139240
ENSE00003517165	78132788	78132870
ENSE00003559176	78133853	78134000
ENSE00003559988	78137717	78137814
ENSE00003637340	78133406	78133542
ENSE00003658665	78132359	78132508

Expression profiles

Bgee: expression breadth ubiquitous, 209 present calls, max score 99.11.

FANTOM5 (CAGE): breadth broad, TPM avg 14.9326 / max 699.1161, expressed in 580 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163026	14.2638	570
163025	0.6562	183
163029	0.0125	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.11	gold quality
spleen	UBERON:0002106	97.80	gold quality
vermiform appendix	UBERON:0001154	97.18	gold quality
lymph node	UBERON:0000029	97.07	gold quality
blood	UBERON:0000178	95.84	gold quality
thymus	UBERON:0002370	95.55	gold quality
caecum	UBERON:0001153	94.51	gold quality
ileal mucosa	UBERON:0000331	94.34	gold quality
bone marrow cell	CL:0002092	92.72	gold quality
leukocyte	CL:0000738	92.48	gold quality
monocyte	CL:0000576	92.07	gold quality
superficial temporal artery	UBERON:0001614	91.98	gold quality
bone marrow	UBERON:0002371	91.26	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.34	gold quality
trabecular bone tissue	UBERON:0002483	87.81	gold quality
tonsil	UBERON:0002372	87.73	gold quality
small intestine	UBERON:0002108	87.30	gold quality
epithelium of nasopharynx	UBERON:0001951	86.96	gold quality
cardia of stomach	UBERON:0001162	86.31	gold quality
upper lobe of left lung	UBERON:0008952	85.81	gold quality
upper lobe of lung	UBERON:0008948	85.23	gold quality
left ventricle myocardium	UBERON:0006566	85.19	gold quality
gall bladder	UBERON:0002110	83.89	gold quality
right lung	UBERON:0002167	81.71	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.64	gold quality
lung	UBERON:0002048	81.60	gold quality
mucosa of transverse colon	UBERON:0004991	81.51	gold quality
pylorus	UBERON:0001166	81.02	gold quality
right coronary artery	UBERON:0001625	80.90	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.70	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	30.45
E-CURD-122	yes	21.26
E-ANND-3	yes	15.11

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

54 targeting TMC8, 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-3924	100.00	72.09	2394
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-1255A	99.74	68.09	744
HSA-MIR-1255B-5P	99.74	68.16	741
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-8077	99.17	66.67	862
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-589-5P	98.72	66.96	927
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-3188	98.58	65.60	878

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 26)

• Mutations in EVER2 are associated with epidermodysplasia verruciformis. (PMID:12426567)
• study reports a novel nonsense mutation of the TMC8 gene in Brazilian patients with epidermodysplasia verruciformis (PMID:17711520)
• Genetic variation in the EVER2 gene is associated with squamous cell carcinoma of the skin (PMID:18224692)
• epidermodysplasia verruciformis in a father and a son with typical histologic and clinical findings that occur in the absence of mutations in EVER1 or EVER2. (PMID:19706093)
• Results underline the possible relevance of the EVER2/TMC8 single nucleotide polymorphism rs7208422 in influencing susceptibility to beta-papillomaviruses and their oncogenic potential. (PMID:21196704)
• Data support the involvement of the TMC6/8 region in cervix cancer susceptibility. (PMID:21387292)
• study describes the presence of two previously unreported homozygous mutations in the EVER2 gene in two Italian epidermodysplasia verruciformis patients, each of whom have already developed more than 10 non-melanoma skin cancers (PMID:22158547)
• EVER proteins appear as key components of the activation-dependent regulation of Zn(2+) concentration in T cells. However, the impact of EVER-deficiency in T cells on EV pathogenesis remains to be elucidated (PMID:22761942)
• EVER2-deficient patients display mild T-cell abnormalities: a significant increase of memory CD4+ and effector memory CD8+ T cells, a bias of the T cell receptor Valphabeta and Vgammadelta repertoires and an increase of skin-homing CD4+ T-cell subsets. (PMID:22903682)
• Ever2 interacts with the N-terminal domain of TRADD, impairs the recruitment of TRAF2 and RIPK1 and promotes apoptosis. (PMID:23429285)
• EV is also a rare autosomal recessive genodermatosis involving susceptibility to human papillomavirus (HPV) infections and squamous cell carcinoma, caused in most cases by homozygous mutations in EVER1 or EVER2. (PMID:23534907)
• We report a case of Merkel cell polyomavirus detection in the skin of a patient with epidermodysplasia verruciformis (EDV) and a family history remarkable for an unusual inheritance pattern for EDV. (PMID:23535066)
• Loss of the HPV-infection resistance EVER2 protein impairs NF-kappaB signaling pathways in keratinocytes. (PMID:24586810)
• TMC8 was found to be localized in the endoplasmic reticulum (ER), where it inhibited receptor mediated Ca(2+) release, activation of Ano1 and volume regulated LRRC8-related Cl(-) currents. (PMID:25220380)
• Expression of both EVER1 and EVER2 in B cells is activated immediately after Epstein-Barr virus (EBV) infection, whereas at later stages, it is strongly repressed by latent membrane protein 1-activated NF-kappaB signaling. (PMID:25378492)
• We found a possible correlation between the EVER2 TT genotype and the development of AK, suggesting a potential role of this polymorphism in the development of AK. (PMID:25495765)
• A common genetic variation in TMC8 is associated with high-risk HPV infection and head and neck squamous cell carcinoma etiology. (PMID:25853559)
• Findings suggest that SNPs in EVER2 may be involved in the development of premalignant skin lesions that harbour beta-HPV, perhaps giving rise to SCC tumours that have lost beta-HPV gene expression during progression. (PMID:26126409)
• TMC6/EVER1 and TMC8/EVER2 are known to be involved in the development of EV. (PMID:26227733)
• There were no differences in Ever2 SNPs between head and neck squamous cell carcinoma patients with human papilloma virus (HPV)-positive and HPV-negative tumors, and healthy controls. (PMID:27097911)
• The present study did not show any significant association of the EVER1/2 polymorphisms (rs2290907and rs16970849) with cervical cancer. (PMID:27899077)
• The relatively high proportion of EV patients without mutation in TMC6/8 indicates the existence of EV-causing mutations in additional, presently unknown gene(s). However, a homozygous TMC8 splice site mutation in our patients resulted in aberrant transcripts which cannot retain the healthy phenotype (PMID:28646613)
• these findings suggest that the disruption of CIB1-EVER1-EVER2-dependent keratinocyte-intrinsic immunity underlies the selective susceptibility to beta-HPVs of epidermodysplasia verruciformis patients. (PMID:30068544)
• Expression of a TMC6-TMC8-CIB1 heterotrimeric complex in lymphocytes is regulated by each of the components. (PMID:32917726)
• Case of epidermodysplasia verruciformis with a novel mutation of TMC8. (PMID:34459021)
• Establishment of a human induced pluripotent stem cell line, KMUGMCi005-A, from a patient with Epidermodysplasia verruciformis (EV) bearing homozygous splicing donor site mutation in the TMC8 gene. (PMID:36170758)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmc8	ENSDARG00000101050
mus_musculus	Tmc8	ENSMUSG00000050106
rattus_norvegicus	Tmc8	ENSRNOG00000046086
caenorhabditis_elegans		WBGENE00015177
caenorhabditis_elegans		WBGENE00020490

Paralogs (7): TMC5 (ENSG00000103534), TMC6 (ENSG00000141524), TMC2 (ENSG00000149488), TMC1 (ENSG00000165091), TMC4 (ENSG00000167608), TMC7 (ENSG00000170537), TMC3 (ENSG00000188869)

Protein

Protein identifiers

Transmembrane channel-like protein 8 — Q8IU68 (reviewed: Q8IU68)

Alternative names: Epidermodysplasia verruciformis protein 2

All UniProt accessions (1): Q8IU68

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a regulatory protein involved in the regulation of numerous cellular processes. Together with its homolog TMC6/EVER1, forms a complex with calcium-binding protein CIB1 in lymphocytes and keratynocytes where TMC6 and TMC8 stabilize CIB1 levels and reciprocally. Together with TMC6, also forms a complex with and activates zinc transporter ZNT1 at the ER membrane of keratynocytes, thereby facilitating zinc uptake into the ER. Also inhibits receptor-mediated calcium release from ER stores and calcium activated and volume regulated chloride channels. Down-regulates the activity of transcription factors induced by zinc and cytokines. Also sequesters TRADD which impairs the recruitment of TRAF2 and RIPK1 in the pro-survival complex I and promotes proapoptotic complex II formation, and may therefore be involved in TNF-induced cell death/survival decisions.

Subunit / interactions. Interacts with TMC6. Interacts and forms a complex with TMC6 and CIB1; the interaction stabilizes each component of the complex. Interacts and forms a complex with TMC6 and SLC30A1/ZNT1; the interaction regulates zinc transport into the ER. Interacts with TRADD; the interaction competes with TRADD/RIPK1/TRAF2/cIAPs complex I formation and facilites complex II formation. (Microbial infection) Interacts with human papillomavirus 16/HPV16 protein E5; the interaction alleviates TMC8-mediated transcription factors inhibition.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane. Nucleus membrane.

Tissue specificity. Expressed in placenta, prostate and testis.

Disease relevance. Epidermodysplasia verruciformis 2 (EV2) [MIM:618231] A form of epidermodysplasia verruciformis, a rare genodermatosis associated with a high risk of skin carcinoma that results from an abnormal susceptibility to infection by specific human papillomaviruses, including the oncogenic HPV5. Infection leads to the early development of disseminated flat wart-like and pityriasis versicolor-like skin lesions. Cutaneous Bowen’s carcinomas in situ and invasive squamous cell carcinomas develop in about half of the patients, mainly on sun-exposed skin areas. EV2 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The TMC domain mediates the interaction with SLC30A1/ZNT1.

Similarity. Belongs to the TMC family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IU68-1	1, Large EVER2	yes
Q8IU68-2	2, Small EVER2

RefSeq proteins (1): NP_689681* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012496	TMC_dom	Domain
IPR038900	TMC	Family

Pfam: PF07810

UniProt features (31 total): topological domain 9, transmembrane region 8, modified residue 3, sequence variant 3, region of interest 2, glycosylation site 2, chain 1, compositionally biased region 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IU68-F1	76.77	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.

Post-translational modifications (3): 6, 658, 673

Glycosylation sites (2): 148, 567

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 173 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_PROTEIN_BINDING, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, CERVERA_SDHB_TARGETS_1_DN, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, ZHAN_MULTIPLE_MYELOMA_CD1_UP, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_VIA_DEATH_DOMAIN_RECEPTORS, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_BINDING, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_PROTEIN_STABILIZATION

GO Biological Process (11): intracellular zinc ion homeostasis (GO:0006882), regulation of tumor necrosis factor-mediated signaling pathway (GO:0010803), negative regulation of protein-containing complex assembly (GO:0031333), negative regulation of protein binding (GO:0032091), positive regulation of apoptotic process (GO:0043065), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), protein stabilization (GO:0050821), regulation of extrinsic apoptotic signaling pathway via death domain receptors (GO:1902041), tumor necrosis factor-mediated signaling pathway (GO:0033209), monoatomic ion transmembrane transport (GO:0034220), positive regulation of canonical NF-kappaB signal transduction (GO:0043123)

GO Molecular Function (4): mechanosensitive monoatomic ion channel activity (GO:0008381), tumor necrosis factor binding (GO:0043120), protein sequestering activity (GO:0140311), protein binding (GO:0005515)

GO Cellular Component (11): Golgi membrane (GO:0000139), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), nuclear membrane (GO:0031965), extracellular exosome (GO:0070062), nucleus (GO:0005634), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
protein binding	2
canonical NF-kappaB signal transduction	2
regulation of canonical NF-kappaB signal transduction	2
cellular anatomical structure	2
cytoplasm	2
endomembrane system	2
organelle membrane	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
regulation of cytokine-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
regulation of protein-containing complex assembly	1
negative regulation of cellular component organization	1
protein-containing complex assembly	1
regulation of protein binding	1
negative regulation of binding	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
negative regulation of intracellular signal transduction	1
regulation of protein stability	1
extrinsic apoptotic signaling pathway via death domain receptors	1
regulation of extrinsic apoptotic signaling pathway	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
monoatomic ion transport	1
transmembrane transport	1
positive regulation of intracellular signal transduction	1
monoatomic ion channel activity	1
gated channel activity	1
cytokine binding	1
molecular sequestering activity	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
intracellular anatomical structure	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1

Protein interactions and networks

STRING

1256 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMC8	SLC30A1	Q9Y6M5	964
TMC8	SYNGR2	O43760	922
TMC8	TK1	P04183	750
TMC8	CANX	P27824	722
TMC8	CIB1	Q99828	696
TMC8	TMC6	Q7Z403	642
TMC8	CORO1A	P31146	546
TMC8	RHOH	Q15669	529
TMC8	DOCK8	Q8NF50	477
TMC8	KCNG4	Q8TDN1	406
TMC8	RCSD1	Q6JBY9	406
TMC8	YIPF4	Q9BSR8	405
TMC8	ZNF324B	Q6AW86	400
TMC8	IDUA	P35475	385
TMC8	PRKX	P51817	377

IntAct

1 interactions, top by confidence:

BioGRID (14): TRAF1 (Affinity Capture-Western), TRAF2 (Affinity Capture-Western), TMC8 (Affinity Capture-Western), TMC8 (Affinity Capture-Western), TRADD (PCA), TMC8 (Proximity Label-MS), TMC8 (Affinity Capture-RNA), SLC30A1 (Reconstituted Complex), SLC30A1 (Affinity Capture-Western), TMC8 (Affinity Capture-Western), TMC8 (Co-localization), TMC8 (Affinity Capture-Western), CIB1 (Affinity Capture-Western), CIB1 (Co-localization)

ESM2 similar proteins: A1A5B4, A2AHL1, A2BIE7, A2RRU4, A5PK40, A6NDV4, A6QLK4, A6QM06, B1AWJ5, E9PTA2, E9Q6C8, O94759, P86044, P97260, Q04671, Q12770, Q17QL9, Q3TD49, Q49LS8, Q4R7X9, Q5F383, Q5GH57, Q5MNU5, Q5PQL3, Q5RBY7, Q5ZMP3, Q60HE8, Q6AY05, Q6GQT6, Q6UX01, Q7RTT9, Q7TN60, Q7Z403, Q8IU68, Q8MIQ9, Q8N4M1, Q8R139, Q8R4F0, Q8TCT7, Q91YD4

Diamond homologs: A0A0U1QT59, E7FFT2, F1QFU0, F1QZE9, Q32NZ6, Q496Z4, Q4R7U0, Q5M7W4, Q6UXY8, Q7TN58, Q7TQ65, Q7Z402, Q7Z404, Q8C428, Q8IU68, Q8R4P4, Q8R4P5, Q8TDI7, Q8TDI8, Q11069, Q5YCC5, D3KZG3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	8
Uncertain significance	240
Likely benign	221
Benign	45

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068639	NM_152468.5(TMC8):c.568C>T (p.Arg190Ter)	Pathogenic
1072560	NM_152468.5(TMC8):c.661_662del (p.Leu221fs)	Pathogenic
1325196	NM_152468.5(TMC8):c.1729G>T (p.Glu577Ter)	Pathogenic
1419566	NM_152468.5(TMC8):c.898del (p.Leu300fs)	Pathogenic
1954704	NM_152468.5(TMC8):c.1207_1208del (p.Lys403fs)	Pathogenic
1961021	NM_152468.5(TMC8):c.423del (p.Asp142fs)	Pathogenic
2029511	NM_152468.5(TMC8):c.871_883del (p.Gln291fs)	Pathogenic
2444390	NM_152468.5(TMC8):c.883_889del (p.Arg295fs)	Pathogenic
2725514	NM_152468.5(TMC8):c.705del (p.Gln236fs)	Pathogenic
2759118	NM_152468.5(TMC8):c.561_583del (p.Ala188fs)	Pathogenic
2835702	NM_152468.5(TMC8):c.1274del (p.Glu425fs)	Pathogenic
3005268	NM_152468.5(TMC8):c.697_698del (p.Leu233fs)	Pathogenic
3686340	NM_152468.5(TMC8):c.1028del (p.Val343fs)	Pathogenic
3717356	NM_152468.5(TMC8):c.752_765del (p.Asp251fs)	Pathogenic
4293115	NM_152468.5(TMC8):c.903_910dup (p.Val304fs)	Pathogenic
456001	NC_000017.11:g.(?78137697)(78137834_?)del	Pathogenic
4711030	NM_152468.5(TMC8):c.1022dup (p.Gly342fs)	Pathogenic
4730718	NM_152468.5(TMC8):c.1263del (p.Ser422fs)	Pathogenic
4747	NM_152468.5(TMC8):c.1084G>T (p.Glu362Ter)	Pathogenic
4760179	NM_152468.5(TMC8):c.988G>T (p.Glu330Ter)	Pathogenic
658615	NM_152468.5(TMC8):c.1746del (p.Leu583fs)	Pathogenic
959535	NM_152468.5(TMC8):c.1268dup (p.Glu425fs)	Pathogenic
1522815	NM_152468.5(TMC8):c.987+2T>A	Likely pathogenic
2001621	NM_152468.5(TMC8):c.1534-1G>C	Likely pathogenic
2193864	NM_152468.5(TMC8):c.987+1G>A	Likely pathogenic
2919330	NM_152468.5(TMC8):c.1664+1G>A	Likely pathogenic
3677282	NM_152468.5(TMC8):c.668+1G>A	Likely pathogenic
935805	NM_152468.5(TMC8):c.449-1G>T	Likely pathogenic
962520	NM_152468.5(TMC8):c.1128-2A>G	Likely pathogenic
967152	NM_152468.5(TMC8):c.669-2A>C	Likely pathogenic

SpliceAI

2874 predictions. Top by Δscore:

Variant	Effect	Δscore
17:78132355:GCAG:G	acceptor_loss	1.0000
17:78132356:CA:C	acceptor_loss	1.0000
17:78132357:A:AG	acceptor_gain	1.0000
17:78132358:G:GG	acceptor_gain	1.0000
17:78132447:C:G	donor_gain	1.0000
17:78132504:CTTGA:C	donor_gain	1.0000
17:78132505:TTGA:T	donor_gain	1.0000
17:78132507:GA:G	donor_gain	1.0000
17:78132509:G:GG	donor_gain	1.0000
17:78132513:GT:G	donor_gain	1.0000
17:78134013:G:GG	donor_gain	1.0000
17:78134543:G:GG	donor_gain	1.0000
17:78134553:G:GT	donor_gain	1.0000
17:78134867:CA:C	acceptor_loss	1.0000
17:78134868:A:AG	acceptor_gain	1.0000
17:78134868:A:AT	acceptor_loss	1.0000
17:78134868:AG:A	acceptor_gain	1.0000
17:78134869:G:GA	acceptor_loss	1.0000
17:78134869:G:GC	acceptor_gain	1.0000
17:78134869:GG:G	acceptor_gain	1.0000
17:78134869:GGA:G	acceptor_gain	1.0000
17:78134869:GGAGT:G	acceptor_gain	1.0000
17:78135005:ATCTG:A	donor_gain	1.0000
17:78135006:TCTG:T	donor_gain	1.0000
17:78135008:TG:T	donor_gain	1.0000
17:78135008:TGGTG:T	donor_loss	1.0000
17:78135009:GG:G	donor_gain	1.0000
17:78135009:GGTG:G	donor_loss	1.0000
17:78135010:G:GG	donor_gain	1.0000
17:78137321:GCT:G	donor_gain	1.0000

AlphaMissense

4614 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:78137257:A:C	S384R	0.994
17:78137259:C:A	S384R	0.994
17:78137259:C:G	S384R	0.994
17:78137722:G:C	W419C	0.994
17:78137722:G:T	W419C	0.994
17:78133932:T:A	W250R	0.988
17:78133932:T:C	W250R	0.988
17:78138060:T:C	F469L	0.987
17:78138062:C:A	F469L	0.987
17:78138062:C:G	F469L	0.987
17:78138731:A:C	S608R	0.986
17:78139162:C:A	S608R	0.986
17:78139162:C:G	S608R	0.986
17:78133934:G:C	W250C	0.985
17:78133934:G:T	W250C	0.985
17:78132388:T:C	F110L	0.981
17:78132390:C:A	F110L	0.981
17:78132390:C:G	F110L	0.981
17:78138117:G:C	G488R	0.981
17:78138602:T:C	F565L	0.981
17:78138604:C:A	F565L	0.981
17:78138604:C:G	F565L	0.981
17:78138603:T:G	F565C	0.980
17:78137724:A:T	E420V	0.979
17:78138061:T:G	F469C	0.979
17:78133938:T:C	F252L	0.978
17:78133940:C:A	F252L	0.978
17:78133940:C:G	F252L	0.978
17:78138111:T:A	W486R	0.978
17:78138111:T:C	W486R	0.978

dbSNP variants (sampled 300 via entrez): RS1000436167 (17:78141929 C>A,G), RS1000511732 (17:78143308 C>T), RS1000691877 (17:78136506 T>C), RS1000998732 (17:78137933 C>T), RS1001003146 (17:78142527 C>T), RS1001485501 (17:78131539 T>A,C), RS1001537919 (17:78132087 A>G), RS1001567389 (17:78142905 A>T), RS1001692639 (17:78133132 A>G), RS1001723568 (17:78132788 C>T), RS1001880103 (17:78133257 A>G), RS1002160081 (17:78138180 A>G,T), RS1002572104 (17:78141886 C>T), RS1002758195 (17:78137229 C>T), RS1002947500 (17:78136996 G>A)

Disease associations

OMIM: gene MIM:605829 | disease phenotypes: MIM:618231, MIM:226400

GenCC curated gene-disease

Disease	Classification	Inheritance
epidermodysplasia verruciformis, susceptibility to, 2	Definitive	Autosomal recessive
epidermodysplasia verruciformis	Supportive	Autosomal recessive

Mondo (3): epidermodysplasia verruciformis (MONDO:0009176), epidermodysplasia verruciformis, susceptibility to, 2 (MONDO:0032614), epidermodysplasia verruciformis, susceptibility to, 1 (MONDO:0100045)

Orphanet (1): Inherited epidermodysplasia verruciformis (Orphanet:302)

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001051	Seborrheic dermatitis
HP:0001053	Hypopigmented skin patches
HP:0001581	Recurrent skin infections
HP:0002715	Abnormality of the immune system
HP:0002860	Squamous cell carcinoma
HP:0006739	Squamous cell carcinoma of the skin
HP:0007565	Multiple cafe-au-lait spots
HP:0020114	Persistent human papillomavirus infection
HP:0100585	Telangiectasia of the skin
HP:0200034	Papule
HP:0200035	Skin plaque
HP:0200039	Pustule
HP:0200043	Verrucae
HP:0550004	Verruca plana

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST004611_134	High light scatter reticulocyte count	4.000000e-10
GCST004612_82	High light scatter reticulocyte percentage of red cells	3.000000e-11
GCST004619_77	Reticulocyte fraction of red cells	2.000000e-10
GCST005145_3	Glycated hemoglobin levels	5.000000e-20
GCST012133_2	hemolysis of donated blood (cold-storage)	1.000000e-08
GCST90002385_327	High light scatter reticulocyte count	7.000000e-23
GCST90002386_76	High light scatter reticulocyte percentage of red cells	5.000000e-27
GCST90002390_539	Mean corpuscular hemoglobin	4.000000e-12
GCST90002392_32	Mean corpuscular volume	2.000000e-17
GCST90002397_588	Mean spheric corpuscular volume	1.000000e-12
GCST90002403_323	Red blood cell count	4.000000e-10
GCST90002404_180	Red cell distribution width	1.000000e-23
GCST90002404_181	Red cell distribution width	2.000000e-20
GCST90002405_397	Reticulocyte count	4.000000e-24
GCST90002406_477	Reticulocyte fraction of red cells	5.000000e-31

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0004541	HbA1c measurement
EFO:0009473	hemolysis
EFO:0004527	mean corpuscular hemoglobin
EFO:0004305	erythrocyte count
EFO:0009188	Red cell distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D004819	Epidermodysplasia Verruciformis	C01.925.256.650.810.345; C01.925.825.810.260; C01.925.928.914.345; C17.800.838.790.810.260

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases mutagenesis, decreases methylation, increases methylation	2
Nickel	increases expression	2
sotorasib	affects cotreatment, decreases expression	1
propionaldehyde	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	increases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects expression	1
Azathioprine	increases expression	1
Endosulfan	increases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Silicon Dioxide	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
Cyclosporine	increases expression	1
Antirheumatic Agents	decreases expression	1
Copper Sulfate	increases expression	1
S-Nitrosoglutathione	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C3QT	KMUGMCi005-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00973856	Not specified	COMPLETED	Evaluation of the Effectiveness of an Alcohol Based Hand Gel for the Reduction of Warts on the Hands