SKIC2
protein-codingSKI2 subunit of superkiller complex, the group of SKI complex subunits|Ski2 like RNA helicases
Gene summary
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. [provided by RefSeq, Jul 2008]
- SKIV2
- SKIV2L
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~10.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013818
Submitter: PanelApp Australia
https://panelapp.agha.umccr.org/panels/137/
Inheritance Pattern: AR
Disease ID:MONDO:0013818
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013818
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013818
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009105
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013818
Submitter: ClinGen
The *SKIC2* gene is located on chromosome 6 at 6p21.33 and encodes the SKI2 subunit of superkiller complex, the cytoplasmic co-factor and regulator of the RNA-degrading exosome. *SKIC2* was first reported in relation to autosomal recessive trichohepatoenteric syndrome 2 in 2012 (Fabre et al., PMID: 22444670). Trichohepatoenteric syndrome 2 is characterized by intrauterine growth restriction, facial dysmorphism, hair abnormalities, intractable diarrhea, and immunodeficiency. Twelve variants (five nonsense, three frameshift, three missense, and one indel ) that have been reported in nine probands in two publications (PMIDs: 22444670, 34414925) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by functional alteration of patient cells and an animal model (PMIDs: 25064072, 35658009). In summary, there is definitive evidence supporting the relationship between *SKIC2* and autosomal recessive trichohepatoenteric syndrome 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date April 23rd, 2024 (SOP Version 10).
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Craniofacial; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal
Intervention: Allergy/Immunology/Infectious; Gastrointestinal
Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections can be beneficial; Parenteral nutrition may be required
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SKIC2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006929.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 5 | 341 | 5 | 351 | ||
| missense | 2 | 5 | 376 | 16 | 2 | 401 |
| nonsense | 31 | 9 | 40 | |||
| start loss | 1 | 1 | ||||
| frameshift | 55 | 13 | 1 | 69 | ||
| splice donor/acceptor (+/-2bp) | 2 | 39 | 2 | 1 | 44 | |
| Total | 90 | 66 | 384 | 359 | 7 | 906 |
Highest pathogenic variant AF is 0.000112247784
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_008860.4 | 28 | MANE Select | |
| Ensembl | ENSP00000364543.2 | 28 | MANE Select | |
| Ensembl | ENSP00000419905.1 | 8 | Standard | |
| Ensembl | ENSP00000420470.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- RNA degradation - Homo sapiens (human)
- Metabolism of proteins
- Metabolism of RNA
- Chaperonin-mediated protein folding
- Association of TriC/CCT with target proteins during biosynthesis
Biological Process
- RNA catabolic process
- exonucleolytic nuclear-transcribed mRNA catabolic process involved in deadenylation-dependent decay
- nuclear-transcribed mRNA catabolic process, 3'-5' exonucleolytic nonsense-mediated decay
Molecular Function
- RNA binding
- ATP-dependent RNA helicase activity
- ATP binding
Cellular Component
- nucleus
- cytosol
- Ski complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000375394
- Coding exons
- 28
- Length
- 10676
- Individuals with no LoFs
- 125558
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 190
- Defined
- 125748
- p
- 0.000756
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.85 | 614 | 757 | 0.811 | 0.0000466 | 7995 |
| Missense (PolyPhen) | 225 | 283.48 | 0.79369 | 2913 | ||
| Synonymous | 2.83 | 232 | 294 | 0.790 | 0.0000169 | 2635 |
| Loss of Function | 2.37 | 45 | 65.8 | 0.684 | 0.00000366 | 690 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0011 | 0.0011 | notable |
| Latino/Admixed American | 0.0015 | 0.0015 | notable |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00061 | 0.00060 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00080 | 0.00077 | rare |
| South Asian | 0.00046 | 0.00046 | rare |
| Other | 0.00050 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Helicase; has ATPase activity. Component of the SKI complex which is thought to be involved in exosome-mediated RNA decay and associates with transcriptionally active genes in a manner dependent on PAF1 complex (PAF1C).;
- Disease
- DISEASE: 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. {ECO:0000269|PubMed:22444670}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.965
- RVIS EVS
- 0.17
- RVIS percentile EVS
- 64.98
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.903
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |