TCN2
protein-codingtranscobalamin 2
Gene summary
This gene encodes a member of the vitamin B12-binding protein family. This family of proteins, alternatively referred to as R binders, is expressed in various tissues and secretions. This plasma protein binds cobalamin and mediates the transport of cobalamin into cells. This protein and other mammalian cobalamin-binding proteins, such as transcobalamin I and gastric intrisic factor, may have evolved by duplication of a common ancestral gene. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~20.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0010149
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0010149
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0010149
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0010149
Submitter: ClinGen
*TCN2* was first reported in relation to autosomal recessive transcobalamin II deficiency and megaloblastic anemia in 1971 (Hakami et al., PMID:5096637). This condition is primarly characterized by megaloblastic anemia and often includes phenotypes such as neurologic deficits, neutropenia, pancytopenia, failure to thrive, and recurrent infections. TCN2 deficiency is often accompanied by elevations in methylmalonic acid levels and plasma homocysteine levels. One cohort study from Trakadis YJ, et al. of 30 patients with TCN2 deficiency demonstrated that 17% had agammaglobulinemia, low IgGs, or low T and B cell counts, and 8% had recurrent infections (PMID:24305960). At least 48 variants have been identified in association with TCN2 deficiency (Luo et al., PMID: 36035190). In this curation, 12 variants were scored including frameshift, nonsense, and splice site variants across 10 probands from 9 publications (PMIDs: 32841161, 33685478, 35866322, 36035190, 31666257, 20352340, 24305960, 30185401, 33023511). Heterozygous parents and siblings were unaffected. The mechanism of pathogenicity is loss of function. This gene-disease association is also supported by the biochemical function of TCN2 (PMID: 7742531).TCN2 is a transport protein that binds vitamin B12 and facilitates its uptake via endocytosis. Phenotypes displayed by patients with TCN2 deficiency are driven by the inability of cells to use vitamin B12. Vitamin B12 and folate are crucial to DNA synthesis. A lack of vitamin B12 causes impaired cell synthesis and manifests with deficits in rapidly dividing cells. It also manifests with elevated methylmalonic acid and homocysteine levels. Phenotypes observed in probands with TCN2 deficiency are in line with deficits consistent with vitamin B12 deficiency including pancytopenia, megaloblastic anemia, and neurologic defects. Additionally, the gene-disease relationship is supported by knock out *TCN2* zebrafish (PMID: 34132337). *TCN2* (-/-) zebrafish displayed phenotypes such as developmental delay and elevated methylmalonic acid levels consistent with vitamin B12 insufficiency. In summary, there is definitive evidence to support this gene-disease relationship. This classification was approved by the SCID-CID GCEP (SOP version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0010149
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0010149
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Biochemical; Gastrointestinal; Hematologic; Neurologic
Intervention: Allergy/Immunology/Infectious; Biochemical
Rationale: The condition can include neurocognitive impairment, hematologic anomalies (eg, anemia, panyctopenia), susceptibility to recurrent and severe infections, and gastrointestinal sequelae, and cobalamin treatment can result in prevention and/or clinical improvement, including related to developmental parameters; Awareness of immunodeficiency may allow prompt treatment of infections
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TCN2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000355.4. 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 | 6 | 201 | 2 | 209 | ||
| missense | 235 | 23 | 3 | 261 | ||
| nonsense | 13 | 5 | 1 | 19 | ||
| start loss | 1 | 1 | ||||
| frameshift | 32 | 7 | 39 | |||
| splice donor/acceptor (+/-2bp) | 3 | 12 | 15 | |||
| Total | 49 | 24 | 242 | 224 | 5 | 544 |
Highest pathogenic variant AF is 0.00029429587
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000346.2 | 9 | MANE Select | |
| Ensembl | ENSP00000215838.3 | 9 | MANE Select | |
| RefSeq | NP_001171655.1 | 9 | Standard | |
| Ensembl | ENSP00000385914.3 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Vitamin digestion and absorption - Homo sapiens (human)
- Vitamin B12 Metabolism
- One Carbon Metabolism
- Cobalamin (Cbl, vitamin B12) transport and metabolism
- Metabolism
Biological Process
- cobalt ion transport
- cobalamin metabolic process
- cobalamin transport
Molecular Function
- protein binding
- cobalamin binding
- metal ion binding
Cellular Component
- extracellular region
- extracellular space
- endosome
- lysosomal lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000215838
- Coding exons
- 9
- Length
- 20441
- Individuals with no LoFs
- 125675
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 73
- Defined
- 125748
- p
- 0.000290
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -2.12 | 322 | 231 | 1.39 | 0.0000128 | 2760 |
| Missense (PolyPhen) | 95 | 73.17 | 1.2983 | 965 | ||
| Synonymous | -4.19 | 149 | 96.6 | 1.54 | 0.00000543 | 873 |
| Loss of Function | 1.81 | 13 | 22.2 | 0.585 | 0.00000133 | 232 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00055 | 0.00055 | rare |
| Latino/Admixed American | 0.00020 | 0.00020 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00037 | 0.00036 | rare |
| South Asian | 0.00026 | 0.00026 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Primary vitamin B12-binding and transport protein. Delivers cobalamin to cells. {ECO:0000269|PubMed:8443384}.;
- Disease
- DISEASE: Transcobalamin II deficiency (TCN2 deficiency) [MIM:275350]: Results in various forms of anemia. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.565
Intolerance Scores
- LoFtool
- 0.808
- RVIS EVS
- 1.93
- RVIS percentile EVS
- 97.49
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.411
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |