SKIC2

Summary

SKIC2 (SKI2 subunit of superkiller complex, HGNC:10898) is a protein-coding gene on chromosome 6p21.33, encoding Superkiller complex protein 2 (Q15477). Helicase component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways.

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which is a human homologue of yeast SKI2 and may be involved in antiviral activity by blocking translation of poly(A) deficient mRNAs. This gene is located in the class III region of the major histocompatibility complex.

Source: NCBI Gene 6499 — RefSeq curated summary.

At a glance

• Gene–disease (curated): trichohepatoenteric syndrome 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 40
• Clinical variants (ClinVar): 1,105 total — 83 pathogenic, 35 likely-pathogenic
• Phenotypes (HPO): 64
• MANE Select transcript: NM_006929

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10898
Approved symbol	SKIC2
Name	SKI2 subunit of superkiller complex
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	HLP, DDX13, SKI2W, 170A, SKIV2L1, SKI2
Ensembl gene	ENSG00000204351
Ensembl biotype	protein_coding
OMIM	600478
Entrez	6499

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 17 protein_coding, 12 retained_intron, 6 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

ENST00000375394, ENST00000461073, ENST00000461915, ENST00000465703, ENST00000466290, ENST00000470453, ENST00000471818, ENST00000474839, ENST00000483553, ENST00000484835, ENST00000485349, ENST00000488648, ENST00000491994, ENST00000492900, ENST00000494058, ENST00000697831, ENST00000697832, ENST00000697833, ENST00000697834, ENST00000697835, ENST00000697836, ENST00000697837, ENST00000697838, ENST00000697839, ENST00000697840, ENST00000697841, ENST00000697842, ENST00000858388, ENST00000858389, ENST00000858390, ENST00000858391, ENST00000858392, ENST00000858393, ENST00000938522, ENST00000938523, ENST00000962078, ENST00000962079, ENST00000962080, ENST00000962081

RefSeq mRNA: 1 — MANE Select: NM_006929 NM_006929

CCDS: CCDS4731

Canonical transcript exons

ENST00000375394 — 28 exons

Exon	Start	End
ENSE00003458777	31969280	31969420
ENSE00003466866	31962985	31963091
ENSE00003470430	31964232	31964342
ENSE00003488771	31962439	31962585
ENSE00003514149	31960010	31960119
ENSE00003515290	31960220	31960337
ENSE00003517330	31962714	31962798
ENSE00003517789	31961909	31962054
ENSE00003520023	31968871	31969089
ENSE00003541957	31960666	31960740
ENSE00003558195	31960432	31960546
ENSE00003569101	31961196	31961386
ENSE00003577479	31963637	31963733
ENSE00003579410	31961041	31961094
ENSE00003587727	31963913	31964125
ENSE00003601103	31966709	31966846
ENSE00003602162	31959297	31959400
ENSE00003616452	31963413	31963559
ENSE00003625292	31968686	31968796
ENSE00003640082	31967273	31967377
ENSE00003642456	31967004	31967141
ENSE00003650260	31961547	31961675
ENSE00003674214	31967715	31967862
ENSE00003680573	31965783	31966013
ENSE00003971828	31969515	31969751
ENSE00003971834	31968328	31968538
ENSE00003971847	31959175	31959214
ENSE00003971857	31967956	31968082

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 96.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.9259 / max 324.9993, expressed in 1819 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67103	39.5278	1819
67104	0.3981	170

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	96.44	gold quality
pituitary gland	UBERON:0000007	96.35	gold quality
adenohypophysis	UBERON:0002196	96.14	gold quality
granulocyte	CL:0000094	95.86	gold quality
spleen	UBERON:0002106	95.63	gold quality
right adrenal gland	UBERON:0001233	95.14	gold quality
right adrenal gland cortex	UBERON:0035827	94.91	gold quality
mucosa of transverse colon	UBERON:0004991	94.87	gold quality
right lobe of thyroid gland	UBERON:0001119	94.86	gold quality
fundus of stomach	UBERON:0001160	94.85	gold quality
blood	UBERON:0000178	94.74	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.71	gold quality
apex of heart	UBERON:0002098	94.70	gold quality
left adrenal gland	UBERON:0001234	94.43	gold quality
prostate gland	UBERON:0002367	94.40	gold quality
left adrenal gland cortex	UBERON:0035825	94.33	gold quality
left lobe of thyroid gland	UBERON:0001120	94.25	gold quality
small intestine	UBERON:0002108	94.20	gold quality
endocervix	UBERON:0000458	94.18	gold quality
thyroid gland	UBERON:0002046	94.18	gold quality
liver	UBERON:0002107	94.07	gold quality
left uterine tube	UBERON:0001303	94.06	gold quality
right ovary	UBERON:0002118	94.06	gold quality
body of stomach	UBERON:0001161	94.00	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.00	gold quality
adrenal gland	UBERON:0002369	93.99	gold quality
mucosa of stomach	UBERON:0001199	93.83	gold quality
metanephros cortex	UBERON:0010533	93.74	gold quality
lower esophagus mucosa	UBERON:0035834	93.71	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.62

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 12)

• SKI2VL was found to be associated with the human exosome, a multiprotein complex involved in RNA degradation. (PMID:11719186)
• Our results do not support any major role of the 4 AMD-associated variants in the risk of developing PCV, but favor a predominant association with the RDBP-SKIV2L variants (PMID:19556007)
• A protective effect was observed at rs429608, an intronic SNP in SKIV2L. (PMID:20861866)
• The results showed that mutations in genes encoding SKIV2L cause trichohepatoenteric syndrome, establishing a link between defects of the human exosome complex and a Mendelian disease. (PMID:22444670)
• SKIV2L is a likely causal gene for neovascular AMD, conferring a significant protective effect independent of CFH and HTRA1. (PMID:23260260)
• Novel homozygous frameshift mutations in the AKR1D1 gene and in the SKIV2L gene were found in a family with severe infantile liver disease. (PMID:23679950)
• A SKIV2L variant was associated with protection against exudative age-related macular degeneration regardless of subtypes in the Japanese population. (PMID:24865191)
• Data from 4 consanguineous families in Saudi Arabia suggest SKIV2L mutations in tricho-hepato-enteric syndrome can include deletions (c.3559_3579del, p.1187_1193del; 4 subjects) and nonsense mutation (c.C4102T, p.Q1368X; 1 subject). [CASE REPORT] (PMID:25714577)
• Study reported three point mutations, which have not been previously described in other patients with THES in SKIV2L and TTC37 genes, including one nonsense, one frameshift, and one missense mutations. (PMID:27050310)
• The present study was the first, to the best of our knowledge, to report a case of a boy with THES resulting from compound heterozygous mutations of the SKIV2L gene in China. (PMID:27431780)
• This meta-analysis showed that SKIV2L rs429608 was statistically associated with age-related macular degeneration(AMD) and it might exert a protective effect on AMD. Further investigations are needed to validate the association and confirm the role of SKIV2L in AMD. (PMID:27484132)
• We then examined the lab diagnostic cohort in detail for clinical manifestations. For the first time, we are able to suggest that patients lacking SKIV2L seem more severely affected than those lacking TTC37, in terms of liver damage and prenatal growth impairment. (PMID:29527791)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	skic2	ENSDARG00000062206
mus_musculus	Skic2	ENSMUSG00000040356
rattus_norvegicus	Skic2	ENSRNOG00000000421
drosophila_melanogaster	tst	FBGN0039117
caenorhabditis_elegans		WBGENE00008502

Paralogs (8): MTREX (ENSG00000039123), POLQ (ENSG00000051341), ASCC3 (ENSG00000112249), DDX60 (ENSG00000137628), SNRNP200 (ENSG00000144028), HFM1 (ENSG00000162669), HELQ (ENSG00000163312), DDX60L (ENSG00000181381)

Protein

Protein identifiers

Superkiller complex protein 2 — Q15477 (reviewed: Q15477)

Alternative names: Helicase-like protein

All UniProt accessions (12): Q15477, A0A1U9X8J1, A0A8V8TL97, A0A8V8TLA2, A0A8V8TLC0, A0A8V8TLR3, A0A8V8TMR3, A0A8V8TN04, B4E0B4, F8WDE8, H7C4L3, H7C5N0

UniProt curated annotations — full annotation on UniProt →

Function. Helicase component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways. The SKI complex catalyzes mRNA extraction from 80S ribosomal complexes in the 3’-5’ direction and channels mRNA to the cytosolic exosome for degradation. SKI-mediated extraction of mRNA from stalled ribosomes allow binding of the Pelota-HBS1L complex and subsequent ribosome disassembly by ABCE1 for ribosome recycling. In the nucleus, the SKI complex associates with transcriptionally active genes in a manner dependent on PAF1 complex (PAF1C). May play a role in the non-stop mRNA decay pathway (NSD), which specifically targets and degrades mRNAs that lack a proper stop codon.

Subunit / interactions. Component of the SKI complex which consists of SKIC2, SKIC3 and SKIC8. Interacts with HBS1L isoform 2. Interacts with ANGEL1.

Subcellular location. Nucleus. Cytoplasm.

Disease relevance. Trichohepatoenteric syndrome 2 (THES2) [MIM:614602] A syndrome characterized by intrauterine growth retardation, severe diarrhea in infancy requiring total parenteral nutrition, facial dysmorphism, immunodeficiency, and hair abnormalities, mostly trichorrhexis nodosa. Hepatic involvement contributes to the poor prognosis of affected patients. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the helicase family. SKI2 subfamily.

RefSeq proteins (1): NP_008860* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001650	Helicase_C-like	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR012961	Ski2/MTR4_C	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR016438	FRH-like	Family
IPR025696	Beta-barrel_MTR4	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR040801	Ski2_N	Domain
IPR048392	MTR4-like_stalk	Domain
IPR050699	SUPV3-like	Family

Pfam: PF00270, PF00271, PF08148, PF13234, PF17911, PF21408

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (129 total): helix 50, strand 37, turn 19, sequence variant 11, sequence conflict 3, domain 2, modified residue 2, chain 1, mutagenesis site 1, region of interest 1, short sequence motif 1, binding site 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
7QDY	ELECTRON MICROSCOPY	3.1
9G8M	ELECTRON MICROSCOPY	3.3
9G8O	ELECTRON MICROSCOPY	3.4
9G8R	ELECTRON MICROSCOPY	3.4
7QDZ	ELECTRON MICROSCOPY	3.6
7QDR	ELECTRON MICROSCOPY	3.7
9G8N	ELECTRON MICROSCOPY	3.7
7QDS	ELECTRON MICROSCOPY	3.8
9G8Q	ELECTRON MICROSCOPY	4.1
7QE0	ELECTRON MICROSCOPY	6.5
9G8P	ELECTRON MICROSCOPY	7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15477-F1	81.32	0.41

Functional residue map

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

Ligand- & substrate-binding residues (1): 332–339

Post-translational modifications (2): 245, 256

Mutagenesis-validated functional residues (1):

Position	Phenotype
424	abolished helicase activity.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-390471	Association of TriC/CCT with target proteins during biosynthesis
R-HSA-429958	mRNA decay by 3’ to 5’ exoribonuclease
R-HSA-390466	Chaperonin-mediated protein folding
R-HSA-391251	Protein folding
R-HSA-392499	Metabolism of proteins
R-HSA-429914	Deadenylation-dependent mRNA decay
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 247 (showing top): WANG_CLIM2_TARGETS_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_TRANSLATION, BROWNE_HCMV_INFECTION_14HR_DN, GOBP_TRANSLATIONAL_ELONGATION, NOUZOVA_TRETINOIN_AND_H4_ACETYLATION, GOBP_NUCLEAR_TRANSCRIBED_MRNA_CATABOLIC_PROCESS_NONSENSE_MEDIATED_DECAY, GOBP_ORGANELLE_DISASSEMBLY, REACTOME_METABOLISM_OF_RNA, MODULE_192, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ACID_ANHYDRIDES, YOSHIMURA_MAPK8_TARGETS_UP, GOMF_ATP_HYDROLYSIS_ACTIVITY, GOMF_ADENYL_NUCLEOTIDE_BINDING, GOMF_ISOMERASE_ACTIVITY

GO Biological Process (4): nuclear-transcribed mRNA catabolic process, 3’-5’ exonucleolytic nonsense-mediated decay (GO:0070478), nuclear-transcribed mRNA catabolic process, non-stop decay (GO:0070481), rescue of stalled cytosolic ribosome (GO:0072344), RNA catabolic process (GO:0006401)

GO Molecular Function (10): RNA binding (GO:0003723), RNA helicase activity (GO:0003724), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), 3’-5’ RNA helicase activity (GO:0034458), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), cytosol (GO:0005829), Ski complex (GO:0055087), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Chaperonin-mediated protein folding	1
Deadenylation-dependent mRNA decay	1
Protein folding	1
Metabolism of proteins	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ATP-dependent activity	2
binding	2
cytoplasm	2
cellular anatomical structure	2
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1
nuclear-transcribed mRNA catabolic process	1
cytoplasmic translational elongation	1
ribosome disassembly	1
RNA metabolic process	1
nucleic acid catabolic process	1
nucleic acid binding	1
helicase activity	1
ATP-dependent activity, acting on RNA	1
catalytic activity, acting on RNA	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
RNA helicase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
catalytic activity	1
intracellular membrane-bounded organelle	1
protein-containing complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2603 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SKIC2	SKIC3	Q6PGP7	998
SKIC2	SKIC8	Q9GZS3	998
SKIC2	WHR1	P49842	896
SKIC2	EXOSC1	Q9Y3B2	891
SKIC2	EXOSC3	Q9NQT5	864
SKIC2	DXO	O77932	864
SKIC2	EXOSC5	Q9NQT4	856
SKIC2	EXOSC7	Q15024	855
SKIC2	EXOSC4	Q9NPD3	853
SKIC2	EXOSC6	Q5RKV6	847
SKIC2	EXOSC8	Q96B26	831
SKIC2	XRN2	Q9H0D6	774
SKIC2	XRN1	Q8IZH2	762
SKIC2	EXOSC10	Q01780	760
SKIC2	DCP2	Q8IU60	760

IntAct

74 interactions, top by confidence:

A	B	Type	Score
SKIC8	SKIC2	psi-mi:“MI:0914”(association)	0.710
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
CACNB3	SKIC2	psi-mi:“MI:0915”(physical association)	0.560
PRKAA2	SKIC2	psi-mi:“MI:0915”(physical association)	0.560
NEURL4	APBB1	psi-mi:“MI:0914”(association)	0.530
SKIC8	PFDN6	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
SKIC2	NS1	psi-mi:“MI:0915”(physical association)	0.400
SKIC2	ORF4a	psi-mi:“MI:0915”(physical association)	0.400
SKIC2	SKIC3	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
SKIC2	CDKL5	psi-mi:“MI:0915”(physical association)	0.370
SKIC2	TSSK2	psi-mi:“MI:0915”(physical association)	0.370
Rpl35	RPS6	psi-mi:“MI:0914”(association)	0.350
Eif3a	RPSA	psi-mi:“MI:0914”(association)	0.350
RPL10	RPS6	psi-mi:“MI:0914”(association)	0.350
Rrbp1	PIPSL	psi-mi:“MI:0914”(association)	0.350
RAB4B	NSF	psi-mi:“MI:0914”(association)	0.350
NPM1	RPSA	psi-mi:“MI:0914”(association)	0.350
NEURL4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
IRF2	VWA8	psi-mi:“MI:0914”(association)	0.350
MAP3K14	IKBKG	psi-mi:“MI:0914”(association)	0.350
OASL	LARP1	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
PA	ESYT2	psi-mi:“MI:0914”(association)	0.350
FMR1	MYO1C	psi-mi:“MI:0914”(association)	0.350

BioGRID (141): SKIV2L (Affinity Capture-MS), ALYREF (Co-fractionation), CBS (Co-fractionation), RAN (Co-fractionation), SKIV2L (Co-fractionation), SKIV2L (Co-fractionation), TTC37 (Co-fractionation), SKIV2L (Affinity Capture-MS), SKIV2L (Affinity Capture-MS), SKIV2L (Affinity Capture-MS), SKIV2L (Affinity Capture-MS), SKIV2L (Affinity Capture-MS), SKIV2L (Affinity Capture-MS), SKIV2L (Affinity Capture-MS), SKIV2L (Reconstituted Complex)

ESM2 similar proteins: A0A8C2MDK8, A7SLX5, A7YY46, D3ZEY4, D3ZX08, E9QAM5, O59713, O95822, P0C7A1, P48760, P52333, P52824, Q002B5, Q07071, Q14397, Q15477, Q2KI24, Q2M296, Q2NKY8, Q3SYT1, Q3T7C9, Q3U1Y4, Q3URQ7, Q4R380, Q52L34, Q567W6, Q568Y2, Q5I0I8, Q5NCQ5, Q5ZHX9, Q6GPQ5, Q6NZR5, Q6P5E8, Q8BUI3, Q8BX80, Q8C9A2, Q8NFF5, Q8NFI3, Q91X44, Q920F5

Diamond homologs: A3MSA1, B9DFG3, D0KN27, F0LJX3, F0NDL2, F4JAA5, O13799, O14232, O59801, P35207, P42285, P47047, P51979, P9WMR0, P9WMR1, Q15477, Q23223, Q5H9U9, Q6NZR5, Q8IY21, Q97VY9, Q9CZU3, Q9P7T8, Q9XIF2, Q9ZBD8, Q9ZVW2, A2PYH4, A7IB61, B6DMK2, D3Z4R1, E1BNG3, E9PZJ8, F1LNJ2, F1LPQ2, F1NTD6, H2KY86, O48534, O60072, O75417, O75643

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 101 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SARS-CoV-2 modulates host translation machinery	5	16.5×	1e-03
Formation of the ternary complex, and subsequently, the 43S complex	5	15.8×	1e-03
Translation initiation complex formation	5	14.0×	1e-03
Ribosomal scanning and start codon recognition	5	14.0×	1e-03
SARS-CoV-1-host interactions	5	12.9×	1e-03
SARS-CoV-2-host interactions	7	12.2×	4e-04
rRNA processing in the nucleus and cytosol	5	11.8×	1e-03
rRNA processing	5	10.8×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
ribosomal small subunit biogenesis	6	15.7×	1e-03
negative regulation of translation	6	13.5×	1e-03
cytoplasmic translation	5	10.6×	9e-03
translation	7	8.3×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1105 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	83
Likely pathogenic	35
Uncertain significance	364
Likely benign	531
Benign	28

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323596	NM_006929.5(SKIC2):c.3187C>T (p.Arg1063Ter)	Pathogenic
1323597	NM_006929.5(SKIC2):c.1452del (p.Val485fs)	Pathogenic
1325073	NM_006929.5(SKIC2):c.1992del (p.Phe665fs)	Pathogenic
1365489	NM_006929.5(SKIC2):c.1583_1584del (p.Arg528fs)	Pathogenic
1381311	NM_006929.5(SKIC2):c.427C>T (p.Gln143Ter)	Pathogenic
1404783	NM_006929.5(SKIC2):c.2033_2034dup (p.Asp679fs)	Pathogenic
1417028	NM_006929.5(SKIC2):c.1645C>T (p.Gln549Ter)	Pathogenic
1417038	NM_006929.5(SKIC2):c.1612del (p.Ala538fs)	Pathogenic
1708562	NM_006929.5(SKIC2):c.1891G>A (p.Gly631Ser)	Pathogenic
1805097	NM_006929.5(SKIC2):c.510_511insAGCTGAACACACGG (p.Glu171delinsSerTer)	Pathogenic
1929382	NM_006929.5(SKIC2):c.2479C>T (p.Arg827Ter)	Pathogenic
1956140	NM_006929.5(SKIC2):c.451C>T (p.Gln151Ter)	Pathogenic
1959248	NM_006929.5(SKIC2):c.2457dup (p.Glu820fs)	Pathogenic
1986392	NM_006929.5(SKIC2):c.3055del (p.Arg1019fs)	Pathogenic
2007999	NM_006929.5(SKIC2):c.1631del (p.Gln544fs)	Pathogenic
2008755	NM_006929.5(SKIC2):c.2107_2116del (p.Arg703fs)	Pathogenic
2034489	NM_006929.5(SKIC2):c.1631_1632del (p.Gln544fs)	Pathogenic
2037275	NM_006929.5(SKIC2):c.464G>A (p.Trp155Ter)	Pathogenic
2056766	NM_006929.5(SKIC2):c.377del (p.Leu126fs)	Pathogenic
2086017	NM_006929.5(SKIC2):c.2845C>T (p.Gln949Ter)	Pathogenic
2136372	NM_006929.5(SKIC2):c.2266C>T (p.Arg756Ter)	Pathogenic
2152010	NM_006929.5(SKIC2):c.1528C>T (p.Arg510Ter)	Pathogenic
2695859	NM_006929.5(SKIC2):c.2009del (p.Asn670fs)	Pathogenic
2709650	NM_006929.5(SKIC2):c.3234del (p.Arg1079fs)	Pathogenic
2713958	NM_006929.5(SKIC2):c.2896C>T (p.Gln966Ter)	Pathogenic
2722716	NM_006929.5(SKIC2):c.239_240del (p.Lys80fs)	Pathogenic
2734837	NM_006929.5(SKIC2):c.1420C>T (p.Gln474Ter)	Pathogenic
2734838	NM_006929.5(SKIC2):c.2203-1G>C	Pathogenic
2734840	NM_006929.5(SKIC2):c.2442G>A (p.Trp814Ter)	Pathogenic
2744028	NM_006929.5(SKIC2):c.1754_1760del (p.Gly585fs)	Pathogenic

SpliceAI

3502 predictions. Top by Δscore:

Variant	Effect	Δscore
6:31959192:G:GT	donor_gain	1.0000
6:31959396:GTAGC:G	donor_gain	1.0000
6:31959399:GC:G	donor_gain	1.0000
6:31959401:G:GG	donor_gain	1.0000
6:31960115:GCCCG:G	donor_gain	1.0000
6:31960216:CCA:C	acceptor_loss	1.0000
6:31960217:CA:C	acceptor_loss	1.0000
6:31960218:A:AG	acceptor_gain	1.0000
6:31960218:A:T	acceptor_loss	1.0000
6:31960219:G:GA	acceptor_gain	1.0000
6:31960219:GA:G	acceptor_gain	1.0000
6:31960219:GAA:G	acceptor_gain	1.0000
6:31960219:GAAA:G	acceptor_gain	1.0000
6:31960219:GAAAA:G	acceptor_gain	1.0000
6:31960334:AGAG:A	donor_loss	1.0000
6:31960335:GAG:G	donor_gain	1.0000
6:31960336:AGGT:A	donor_loss	1.0000
6:31960337:GG:G	donor_loss	1.0000
6:31960338:G:T	donor_loss	1.0000
6:31960427:CTTAG:C	acceptor_loss	1.0000
6:31960428:TTAGG:T	acceptor_loss	1.0000
6:31960661:CCCAG:C	acceptor_loss	1.0000
6:31960663:CAGGG:C	acceptor_loss	1.0000
6:31960664:A:AG	acceptor_gain	1.0000
6:31960664:AG:A	acceptor_gain	1.0000
6:31960664:AGG:A	acceptor_gain	1.0000
6:31960664:AGGG:A	acceptor_gain	1.0000
6:31960664:AGGGG:A	acceptor_gain	1.0000
6:31960665:G:A	acceptor_gain	1.0000
6:31960665:G:GA	acceptor_gain	1.0000

AlphaMissense

8049 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:31961979:T:A	V330D	1.000
6:31962463:G:C	K363N	1.000
6:31962463:G:T	K363N	1.000
6:31962470:A:C	S366R	1.000
6:31962472:C:A	S366R	1.000
6:31962472:C:G	S366R	1.000
6:31962770:A:T	D423V	1.000
6:31962773:A:T	E424V	1.000
6:31962997:T:A	W437R	1.000
6:31962997:T:C	W437R	1.000
6:31962999:G:C	W437C	1.000
6:31962999:G:T	W437C	1.000
6:31963048:A:C	S454R	1.000
6:31963050:T:A	S454R	1.000
6:31963050:T:G	S454R	1.000
6:31963979:T:C	F572L	1.000
6:31963981:C:A	F572L	1.000
6:31963981:C:G	F572L	1.000
6:31965799:A:T	E663V	1.000
6:31965804:T:C	F665L	1.000
6:31965806:T:A	F665L	1.000
6:31965806:T:G	F665L	1.000
6:31965813:G:A	G668R	1.000
6:31965813:G:C	G668R	1.000
6:31966736:T:C	F744L	1.000
6:31966738:C:A	F744L	1.000
6:31966738:C:G	F744L	1.000
6:31961935:G:C	Q315H	0.999
6:31961935:G:T	Q315H	0.999
6:31961942:G:C	A318P	0.999

dbSNP variants (sampled 300 via entrez): RS1000433275 (6:31968827 C>G), RS1000557508 (6:31969129 C>A,T), RS1001022198 (6:31967428 C>G,T), RS1001034715 (6:31967152 G>A,T), RS1001073605 (6:31959803 C>A,T), RS1001708288 (6:31962856 G>A,T), RS1001787153 (6:31968165 C>G,T), RS1002271613 (6:31961684 G>A), RS1002732776 (6:31968697 G>C), RS1003248402 (6:31957432 C>G), RS1003432718 (6:31964678 G>A), RS1005674615 (6:31968134 G>C,T), RS1005814010 (6:31965817 T>A,C), RS1005862514 (6:31959640 T>C), RS1006144217 (6:31960156 G>C)

Disease associations

OMIM: gene MIM:600478 | disease phenotypes: MIM:614602, MIM:222470, MIM:618108

GenCC curated gene-disease

Disease	Classification	Inheritance
trichohepatoenteric syndrome 2	Definitive	Autosomal recessive
trichohepatoenteric syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
trichohepatoenteric syndrome 2	Definitive	AR

Mondo (3): trichohepatoenteric syndrome 2 (MONDO:0013818), trichohepatoenteric syndrome (MONDO:0009105), immunodeficiency 57 (MONDO:0020849)

Orphanet (1): Trichohepatoenteric syndrome (Orphanet:84064)

HPO phenotypes

64 total (30 of 64 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000089	Renal hypoplasia
HP:0000113	Polycystic kidney dysplasia
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000431	Wide nasal bridge
HP:0000501	Glaucoma
HP:0000778	Hypoplasia of the thymus
HP:0000821	Hypothyroidism
HP:0000957	Cafe-au-lait spot
HP:0000958	Dry skin
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001392	Abnormality of the liver
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001622	Premature birth
HP:0001627	Abnormal heart morphology
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001636	Tetralogy of Fallot
HP:0001643	Patent ductus arteriosus
HP:0001647	Bicuspid aortic valve
HP:0001659	Aortic regurgitation
HP:0001744	Splenomegaly
HP:0001888	Decreased total lymphocyte count

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST000806_3	Age-related macular degeneration	5.000000e-15
GCST001942_21	Prostate cancer	5.000000e-09
GCST001986_5	Age-related macular degeneration	7.000000e-07
GCST003219_23	Advanced age-related macular degeneration	1.000000e-103
GCST003219_24	Advanced age-related macular degeneration	3.000000e-06
GCST003219_25	Advanced age-related macular degeneration	9.000000e-12
GCST003219_26	Advanced age-related macular degeneration	3.000000e-10
GCST004131_25	Inflammatory bowel disease	2.000000e-31
GCST004133_79	Ulcerative colitis	5.000000e-65
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_118	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_126	Autism spectrum disorder or schizophrenia	2.000000e-10
GCST004521_154	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_162	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_17	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_173	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_213	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_224	Autism spectrum disorder or schizophrenia	5.000000e-10
GCST004521_227	Autism spectrum disorder or schizophrenia	4.000000e-12
GCST004521_296	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_45	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_81	Autism spectrum disorder or schizophrenia	1.000000e-14
GCST005196_95	Coronary artery disease	6.000000e-13
GCST005359_2	Disease progression in age-related macular degeneration	8.000000e-10
GCST007446_6	vWF levels	3.000000e-08
GCST008916_30	Asthma	1.000000e-09
GCST012227_773	Hip circumference adjusted for BMI	5.000000e-15

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0008336	disease progression measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007789	BMI-adjusted waist circumference
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs429608	SKIC2		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
bisphenol A	increases expression	1
nickel sulfate	increases expression	1
coumarin	decreases phosphorylation	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Temozolomide	increases expression	1
Arsenic	affects methylation	1
Benzene	affects expression	1
Caffeine	decreases phosphorylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Indomethacin	decreases expression, affects cotreatment	1
Ribonucleotides	affects binding	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Cyclosporine	increases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2K4	HAP1 SKIV2L (-) 1	Cancer cell line	Male
CVCL_E2K5	HAP1 SKIV2L (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04499040	Not specified	UNKNOWN	Clinical and Biological Characterization of Patients and Collection of Samples