transcobalamin II deficiency

Summary

transcobalamin II deficiency (MONDO:0010149) is a disease caused by TCN2 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TCN2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 699
• Phenotypes (HPO): 12
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0001919	Acute kidney injury	Very frequent (80-99%)
HP:0001980	Megaloblastic bone marrow	Very frequent (80-99%)
HP:0003220	Abnormality of chromosome stability	Very frequent (80-99%)
HP:0012120	Methylmalonic aciduria	Very frequent (80-99%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0001875	Decreased total neutrophil count	Frequent (30-79%)
HP:0001876	Pancytopenia	Frequent (30-79%)
HP:0001888	Lymphopenia	Frequent (30-79%)
HP:0002720	Decreased circulating IgA level	Frequent (30-79%)
HP:0002850	Decreased circulating total IgM	Frequent (30-79%)
HP:0004313	Decreased circulating antibody level	Frequent (30-79%)
HP:0004315	Decreased circulating IgG level	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	transcobalamin II deficiency
Mondo ID	MONDO:0010149
OMIM	275350
Orphanet	859
DOID	DOID:0050818
ICD-10-CM	D51.2
NCIT	C142806
SNOMED CT	237934001
UMLS	C0342701
MedGen	137976
GARD	0012338
Is cancer (heuristic)	no

Also known as: inherited deficiency of transcobalamin · TCN2 deficiency · transcobalamin II deficiency

Data availability: 699 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › transcobalamin II deficiency

Related subtypes (46): hypersensitivity reaction disease, immune system cancer, immune system organ benign neoplasm, bone marrow disorder, thymus gland disorder, inborn error of immunity, leukocyte disorder, psoriasis, spondyloarthropathy, aggressive insulitis, benign insulitis, inflammatory bowel disease, autoimmune disease, TNF receptor 1-associated periodic fever syndrome, epidermodysplasia verruciformis, Vici syndrome, proteosome-associated autoinflammatory syndrome, hyperimmunoglobulinemia D with periodic fever, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, granulomatosis with polyangiitis, autosomal recessive osteopetrosis 7, graft versus host disease, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, Roifman syndrome, cryopyrin-associated periodic syndrome, anti-HLA hyperimmunization, acquired immunodeficiency, erythroderma desquamativum, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, familial Mediterranean fever, 22q11.2 deletion syndrome, T-cell large granular lymphocyte leukemia, twin to twin transfusion syndrome, immunodeficiency disease, immunoproliferative disorder, cytokine receptor deficiency, immunodeficiency-related disorder, phagocytic cell dysfunction, thrombocytopenic purpura, lymphoid system disorder, immune reconstitution inflammatory syndrome, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, cytokine release syndrome, early-onset autoimmunity-autoinflammation-immunodeficiency syndrome, CADINS disease, autoinflammation, panniculitis, and dermatosis syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

323 likely benign, 160 uncertain significance, 44 pathogenic, 25 benign, 21 conflicting classifications of pathogenicity, 11 benign/likely benign, 9 likely pathogenic, 6 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
100	NM_000355.4(TCN2):c.581-176A>T	TCN2	Pathogenic	no assertion criteria provided
1184573	NM_000355.4(TCN2):c.172del (p.Leu58fs)	TCN2	Pathogenic	no assertion criteria provided
1332781	NM_000355.4(TCN2):c.1003C>T (p.Gln335Ter)	TCN2	Pathogenic	criteria provided, single submitter
1353281	NM_000355.4(TCN2):c.1106+1G>A	TCN2	Pathogenic	criteria provided, multiple submitters, no conflicts
1395597	NM_000355.4(TCN2):c.882del (p.Val295fs)	TCN2	Pathogenic	criteria provided, single submitter
1458198	NC_000022.10:g.(?31003319)(31022508_?)del	TCN2	Pathogenic	criteria provided, single submitter
1675884	NM_000355.4(TCN2):c.997dup (p.Thr333fs)	TCN2	Pathogenic	criteria provided, multiple submitters, no conflicts
1810225	NM_000355.4(TCN2):c.1127dup (p.Leu376fs)	TCN2	Pathogenic	criteria provided, multiple submitters, no conflicts
2138436	NM_000355.4(TCN2):c.937C>T (p.Arg313Ter)	TCN2	Pathogenic	criteria provided, single submitter
2187312	NM_000355.4(TCN2):c.358_359del (p.Arg120fs)	TCN2	Pathogenic	criteria provided, single submitter
2444209	NM_000355.4(TCN2):c.623_624del (p.Arg208fs)	TCN2	Pathogenic	criteria provided, single submitter
2633460	NM_000355.4(TCN2):c.344del (p.Asn115fs)	TCN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2699714	NM_000355.4(TCN2):c.494_495del (p.Cys165fs)	TCN2	Pathogenic	criteria provided, single submitter
2700602	NM_000355.4(TCN2):c.962dup (p.Thr322fs)	TCN2	Pathogenic	criteria provided, single submitter
2707610	NM_000355.4(TCN2):c.380del (p.Leu127fs)	TCN2	Pathogenic	criteria provided, single submitter
2725209	NM_000355.4(TCN2):c.324C>A (p.Tyr108Ter)	TCN2	Pathogenic	criteria provided, single submitter
2737035	NM_000355.4(TCN2):c.679C>T (p.Arg227Ter)	TCN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2745766	NM_000355.4(TCN2):c.632dup (p.Asn212fs)	TCN2	Pathogenic	criteria provided, single submitter
2750346	NM_000355.4(TCN2):c.649_650del (p.Gln217fs)	TCN2	Pathogenic	criteria provided, single submitter
2796652	NM_000355.4(TCN2):c.38del (p.Val13fs)	TCN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2805322	NM_000355.4(TCN2):c.117dup (p.Pro40fs)	TCN2	Pathogenic	criteria provided, single submitter
2810295	NM_000355.4(TCN2):c.420_421del (p.Arg140fs)	TCN2	Pathogenic	criteria provided, single submitter
2812675	NM_000355.4(TCN2):c.1090G>T (p.Glu364Ter)	TCN2	Pathogenic	criteria provided, single submitter
2838618	NM_000355.4(TCN2):c.964dup (p.Thr322fs)	TCN2	Pathogenic	criteria provided, single submitter
2844837	NM_000355.4(TCN2):c.463dup (p.Tyr155fs)	TCN2	Pathogenic	criteria provided, single submitter
2851360	NM_000355.4(TCN2):c.134_155del (p.Leu45fs)	TCN2	Pathogenic	criteria provided, single submitter
2869049	NM_000355.4(TCN2):c.350_351insAC (p.Phe118fs)	TCN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2891030	NM_000355.4(TCN2):c.466C>T (p.Gln156Ter)	TCN2	Pathogenic	criteria provided, single submitter
2897024	NM_000355.4(TCN2):c.324C>G (p.Tyr108Ter)	TCN2	Pathogenic	criteria provided, single submitter
2982426	NM_000355.4(TCN2):c.1033C>T (p.Gln345Ter)	TCN2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TCN2	Definitive	Autosomal recessive	transcobalamin II deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCN2	Orphanet:859	Transcobalamin deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TCN2	HGNC:11653	ENSG00000185339	P20062	Transcobalamin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TCN2	Transcobalamin-2	Primary vitamin B12-binding and transport protein.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCN2	Other/Unknown	no		Cbl-bd_prot, Terpenoid_cyclase/PrenylTrfase, Cobalamin_Transport

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gall bladder	1
metanephros cortex	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCN2	198	ubiquitous	marker	gall bladder, metanephros cortex, right lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TCN2	768

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TCN2	P20062	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective TCN2 causes TCN2 deficiency	1	11420.0×	1e-03	TCN2
Defective CD320 causes MMATC	1	5710.0×	1e-03	TCN2
Transport of RCbl within the body	1	1427.5×	0.003	TCN2
Defects in cobalamin (B12) metabolism	1	815.7×	0.003	TCN2
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	634.4×	0.003	TCN2
Defects in vitamin and cofactor metabolism	1	601.0×	0.003	TCN2
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.009	TCN2
Metabolism of vitamins and cofactors	1	116.5×	0.012	TCN2
Diseases of metabolism	1	80.4×	0.015	TCN2
Disease	1	13.1×	0.084	TCN2
Metabolism	1	11.6×	0.086	TCN2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cobalt ion transport	1	2407.4×	5e-04	TCN2
cobalamin transport	1	1872.4×	5e-04	TCN2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TCN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TCN2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TCN2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns