TCN2

Summary

TCN2 (transcobalamin 2, HGNC:11653) is a protein-coding gene on chromosome 22q12.2, encoding Transcobalamin-2 (P20062). Primary vitamin B12-binding and transport protein.

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.

Source: NCBI Gene 6948 — RefSeq curated summary.

At a glance

• Gene–disease (curated): transcobalamin II deficiency (Definitive, ClinGen)
• GWAS associations: 10
• Clinical variants (ClinVar): 776 total — 55 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 32
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000355

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11653
Approved symbol	TCN2
Name	transcobalamin 2
Location	22q12.2
Locus type	gene with protein product
Status	Approved
Aliases	D22S676, D22S750, TC2
Ensembl gene	ENSG00000185339
Ensembl biotype	protein_coding
OMIM	613441
Entrez	6948

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 19 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay

ENST00000215838, ENST00000405742, ENST00000407817, ENST00000423350, ENST00000450638, ENST00000471659, ENST00000493542, ENST00000698263, ENST00000698264, ENST00000698265, ENST00000698266, ENST00000698267, ENST00000698268, ENST00000698269, ENST00000698270, ENST00000698271, ENST00000698272, ENST00000698273, ENST00000883716, ENST00000883717, ENST00000883718, ENST00000927599, ENST00000947106, ENST00000947107, ENST00000947108

RefSeq mRNA: 2 — MANE Select: NM_000355 NM_000355, NM_001184726

CCDS: CCDS13881, CCDS54519

Canonical transcript exons

ENST00000215838 — 9 exons

Exon	Start	End
ENSE00003470592	30617330	30617495
ENSE00003499331	30622968	30623083
ENSE00003531802	30612873	30613042
ENSE00003568561	30614349	30614501
ENSE00003593728	30615601	30615787
ENSE00003641547	30615301	30615473
ENSE00003646207	30610871	30611063
ENSE00003973167	30607174	30607395
ENSE00003973171	30626460	30627271

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 95.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.3135 / max 1020.3737, expressed in 1594 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191702	9.5506	1412
191706	3.7326	943
191697	1.8847	910
191703	1.5635	590
191705	1.2463	522
191701	0.7069	420
191698	0.6005	352
191699	0.4626	228
191704	0.3376	159
191700	0.2282	104

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gall bladder	UBERON:0002110	95.72	gold quality
metanephros cortex	UBERON:0010533	93.47	gold quality
right lung	UBERON:0002167	92.48	gold quality
adult mammalian kidney	UBERON:0000082	92.20	gold quality
omental fat pad	UBERON:0010414	92.02	gold quality
peritoneum	UBERON:0002358	91.88	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.81	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.15	gold quality
upper lobe of left lung	UBERON:0008952	90.93	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.71	gold quality
right adrenal gland cortex	UBERON:0035827	90.47	gold quality
right adrenal gland	UBERON:0001233	90.13	gold quality
ileal mucosa	UBERON:0000331	90.09	gold quality
left adrenal gland	UBERON:0001234	90.05	gold quality
left uterine tube	UBERON:0001303	89.98	gold quality
left adrenal gland cortex	UBERON:0035825	89.79	gold quality
apex of heart	UBERON:0002098	89.68	gold quality
upper lobe of lung	UBERON:0008948	89.68	gold quality
spleen	UBERON:0002106	89.39	gold quality
rectum	UBERON:0001052	89.33	gold quality
nephron tubule	UBERON:0001231	89.26	gold quality
right coronary artery	UBERON:0001625	89.21	gold quality
small intestine	UBERON:0002108	88.87	gold quality
left coronary artery	UBERON:0001626	88.36	gold quality
left lobe of thyroid gland	UBERON:0001120	88.24	gold quality
monocyte	CL:0000576	88.05	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.01	gold quality
kidney	UBERON:0002113	87.99	gold quality
endocervix	UBERON:0000458	87.94	gold quality
right lobe of thyroid gland	UBERON:0001119	87.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	259.10
E-GEOD-125970	yes	66.98
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, SP3, USF1, USF2

miRNA regulators (miRDB)

18 targeting TCN2, 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-4775	99.98	75.00	6394
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-7155-5P	98.65	66.14	1290
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-6895-5P	97.05	64.96	522
HSA-MIR-4529-5P	96.74	65.77	569
HSA-MIR-3918	96.13	64.65	1300
HSA-MIR-4435	95.90	65.47	1201

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• molecular basis for TCN2 deficiency in two patients with megaloblastic anemia was identified as variance in RNA editing (PMID:12064907)
• determined the influence of TCII genotype on indices of B12 status, including total serum B12, the amount of B12 bound to TCII (holoTCII), methylmalonic acid, and homocysteine (PMID:12091374)
• Transcobalamin II expression is regulated by transcription factor(s) binding to a hexameric sequence (TGGTCC) in the promoter region. (PMID:12413492)
• optimal binding of Cbl by human TC II is supported by disulfide bonds C98-C291 and C147-C187 and that their disruption results in loss of cobalamin binding and their rapid degradation by the proteasomal machinery. (PMID:12660150)
• TCN2 776C>G does not influence holo-Transcobalamin II or vitamin B12 levels, and has no major effect on tHcy concentrations of end-stage renal disease patients. (PMID:12911562)
• Heterozygosity or homozygosity for TCN2 776C>G was not associated with plasma levels of vitamin B, folate, and total homocysteine levels in kidney transplant patients. (PMID:15086930)
• Six common polymorphisms in the TCII gene do not strongly influence risk of neural tube defects in an Irish population. (PMID:15782407)
• transcobalamin 2 is involved in the onset of non-syndromic cleft lip with or without cleft palate (PMID:16470748)
• The results, if confirmed in other populations, highlight the necessity for investigation of the transcobalamin II C776G polymorphism in the research for hyperhomocysteinemia risk factors. (PMID:16820193)
• Given the dramatic heterogeneity of the 776G of TCN2 allele frequency worldwide, this polymorphism may be prone to a selective pressure or confers an evolutionary advantage in confronting environmental factors, one of which is malaria. (PMID:17220211)
• 78% of the patients admitted for first ischemic cerebrovascular attack had low serum holotranscobalomin II levels (PMID:17992530)
• There was no evidence of any association between the RFC1 A80G and TC2 C776G polymorphisms and the maternal risk of Down’s syndrome. (PMID:19274320)
• Transcobalamin II deficiency is associated with megaloblastic anemia. (PMID:19373259)
• Single nucleotide polymorphisms in transcobalamin II gene is associated with mesothelioma. (PMID:19546821)
• these exploratory data provide suggestive evidence for the association of MTHFR 429 Ala/ Ala and TCN2 259 Arg/Arg and CIMP status in colorectal cancer (PMID:19936946)
• Using MMA as a marker for vitamin B12, these results suggest that TCN2 gene variants may lead to decreased vitamin B12 availability, leading to reduced energy metabolism, ultimately contributing to frailty pathology. (PMID:20082058)
• Data show that the TCN2 776CNG genotype exerts a significant influence upon B(12) cellular delivery. (PMID:20144600)
• The association between vitamin B12 and homocysteine concentrations is modified by TC 776 genotype in older Latinos. (PMID:20216556)
• Report TCN2 mutations causing transcobalamin deficiency in a family. (PMID:20607612)
• The TCN2 776C>G polymorphism may contribute to the risk of pathologies associated with a low B(12), and high tHcy phenotype. (PMID:20808328)
• Holotranscobalamin meaesurement does not show superior diagnostic accuracy compared to vitamin B12 for the detection of vitamin B12 deficiency in subjects with neuropsychiatric conditions. (PMID:20890610)
• The G allele of Tc2 c.776C -> G was associated with with higher LDL plasma levels, lower HDL plasma levels, higher triglyceride plasma levels, and higher TC levels. (PMID:20948192)
• structural change of TCII induced by single nucleotide polymorphism (PMID:21214274)
• Maternal 776C>G polymorphism in TCN2 was strongly predictive of NTD in the offspring (p = 0.006). (PMID:21770021)
• genetic association studies in adult populations in Norway: Serum holoTC concentration (but not other indicators of cobalamin status) is lower in TCN2 67AG or 67GG than in 67AA but did not differ among TCN2 776C>G genotypes. (PMID:21865561)
• Variation in the TCN2 gene also affects recurrent stroke risk in response to cofactor therapy (PMID:21975197)
• Three SNPs in transcobalamin II gene (G1196A, C776G and C1043T) are significantly associated with coronary artery disease in Indian population. (PMID:22188304)
• preliminary results indicate that transcobalamin 2 gene polymorphisms can be a susceptibility factor for colorectal cancer (PMID:22794911)
• haplotype association analysis revealed a significant association between idiopathic pulmonary fibrosis and transcobalamin II gene polymorphisms (PMID:23089108)
• observation suggests that the missense variant Tc2. 776C>G influences both neurotoxicity and efficacy of methotrexate in patients with primary central nervous system lymphoma (PMID:23099805)
• Proliferating cancer cells express measurable levels of TCII and TCII-R. (PMID:24122983)
• neither MTHFD G1958A nor TC C776G polymorphisms are an independent risk factor for Down syndrome. However, the combined MTHFD/MTHFR, TC/MTHFR genotypes play a role in the risk of bearing a Down syndrome child in the Chinese population. (PMID:24668664)
• Transcobalamin II (TCN2 67A>G and TCN2 776C>G) and transcobalamin II receptor (TCblR 1104C>T) polymorphisms in Korean patients with idiopathic recurrent spontaneous abortion (PMID:24750446)
• tagSNPs in MTHFR, MTR, MTRR, and TCN2 were not associated with NSCLP in our study, but continued exploration, including allele frequency of various populations and molecular mechanism of the gene-gene interactions of the genes, may provide additional insight into NSCLP. (PMID:25105440)
• TCN2 776C –> G polymorphism is negatively associated with Alzheimer’s type dementia, suggesting a protective role against the disease in subjects with the 5, 10-methylenetetrahydrofolate reductase 1298AA genotype (PMID:25395544)
• There were no other associations between single -nucleotide polymorphisms and the efficacy of MTX treatment. CONCLUSIONS: The MTHFR 677CC and GGH 401TT and CT genotypes were associated with a reduction in the number of MTX-related adverse events. (PMID:25599563)
• Although not significant when corrected for multiple testing, eight single nucleotide polymorphisms (SNPs) in two genes, transcobalamin II (TCN2) and the transcobalamin II-receptor (TCblR), were found to influence several clinical traits of cobalamin deficiency. (PMID:25657319)
• 4 patients with transcobalamin II deficiency were found to have novel mutations, of whom 2 had the same large deletion (homozygous c.1106+1516-1222+1231del). One had c.1107- 347_1222+981delin 364. Another had homozygous c.106C>T. (Q36X). (PMID:25914105)
• Report TCN2 mutations causing transcobalamin deficiency in an Indian patient. (PMID:25947267)
• In Asian populations, the investigated polymorphisms mapping at TCN2 and CBS genes did not provide any evidence of association with cleft lip/cleftpalate. (PMID:26540672)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tcn2	ENSDARG00000036481
mus_musculus	Tcn2	ENSMUSG00000020432
rattus_norvegicus	Tcn2	ENSRNOG00000004280
drosophila_melanogaster	CG3556	FBGN0029708

Paralogs (2): CBLIF (ENSG00000134812), TCN1 (ENSG00000134827)

Protein

Protein identifiers

Transcobalamin-2 — P20062 (reviewed: P20062)

Alternative names: Transcobalamin II

All UniProt accessions (13): A0A8V8TLJ5, A0A8V8TLK0, A0A8V8TLL7, A0A8V8TLM2, A0A8V8TM34, A0A8V8TM37, A0A8V8TN24, A0A8V8TN28, A0A8V8TNC0, A0A8V8TNC5, B5MBX2, P20062, F8WE86

UniProt curated annotations — full annotation on UniProt →

Function. Primary vitamin B12-binding and transport protein. Delivers cobalamin to cells.

Subunit / interactions. Interacts with CD320 (via LDL-receptor class A domains).

Subcellular location. Secreted.

Disease relevance. Transcobalamin II deficiency (TCN2D) [MIM:275350] An autosomal recessive disorder manifesting in early infancy and characterized by failure to thrive, megaloblastic anemia, pancytopenia, and agammaglobulinemia. Additional features include methylmalonic aciduria, recurrent infections, vomiting and diarrhea. TCN2D may be accompanied by neurological complications, including psychomotor and mental developmental delay, if untreated. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the eukaryotic cobalamin transport proteins family.

Isoforms (2)

UniProt ID	Names	Canonical?
P20062-1	1	yes
P20062-2	2

RefSeq proteins (2): NP_000346, NP_001171655 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002157	Cbl-bd_prot	Family
IPR008930	Terpenoid_cyclase/PrenylTrfase	Homologous_superfamily
IPR051588	Cobalamin_Transport	Family

Pfam: PF01122

UniProt features (60 total): helix 17, sequence variant 12, strand 11, binding site 8, turn 5, disulfide bond 4, signal peptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
5NSA	X-RAY DIFFRACTION	1.27
5NP4	X-RAY DIFFRACTION	1.43
5NRP	X-RAY DIFFRACTION	1.57
5NO0	X-RAY DIFFRACTION	1.57
7QBF	X-RAY DIFFRACTION	1.85
4ZRP	X-RAY DIFFRACTION	2.1
4ZRQ	X-RAY DIFFRACTION	2.6
7QBG	X-RAY DIFFRACTION	2.69
7QBE	X-RAY DIFFRACTION	3
2BB5	X-RAY DIFFRACTION	3.2
7QBD	X-RAY DIFFRACTION	4.18

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20062-F1	91.76	0.84

Antibody-complex structures (SAbDab): 4 — 7QBD, 7QBE, 7QBF, 7QBG

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 (8): 104; 152–156; 190–194; 190 (axial binding residue); 242; 245; 291; 395–397

Disulfide bonds (4): 21–267, 83–96, 116–309, 165–205

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-3359454	Defective TCN2 causes TCN2 deficiency
R-HSA-3359485	Defective CD320 causes MMATC
R-HSA-9758890	Transport of RCbl within the body
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-196741	Cobalamin (Cbl, vitamin B12) transport and metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-3296469	Defects in cobalamin (B12) metabolism
R-HSA-3296482	Defects in vitamin and cofactor metabolism
R-HSA-5668914	Diseases of metabolism

MSigDB gene sets: 276 (showing top): WU_APOPTOSIS_BY_CDKN1A_VIA_TP53, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOCC_CELL_SURFACE, SHEPARD_BMYB_MORPHOLINO_DN, GOBP_MONOATOMIC_CATION_TRANSPORT, CEBALLOS_TARGETS_OF_TP53_AND_MYC_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, HNF4_DR1_Q3, ZHAN_V1_LATE_DIFFERENTIATION_GENES_UP, GOBP_VITAMIN_TRANSPORT, MODULE_88, PU1_Q6, MODULE_284, PETROVA_ENDOTHELIUM_LYMPHATIC_VS_BLOOD_DN, TGGNNNNNNKCCAR_UNKNOWN

GO Biological Process (3): cobalt ion transport (GO:0006824), cobalamin transport (GO:0015889), monoatomic ion transport (GO:0006811)

GO Molecular Function (5): cobalamin binding (GO:0031419), metal ion binding (GO:0046872), molecular carrier activity (GO:0140104), cargo receptor ligand activity (GO:0140355), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), lysosomal lumen (GO:0043202)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Defects in cobalamin (B12) metabolism	2
Cobalamin (Cbl, vitamin B12) transport and metabolism	1
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Metabolism	1
Defects in vitamin and cofactor metabolism	1
Diseases of metabolism	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
transition metal ion transport	1
monoatomic cation transmembrane transport	1
vitamin transport	1
nitrogen compound transport	1
transport	1
vitamin binding	1
tetrapyrrole binding	1
heterocyclic compound binding	1
cation binding	1
molecular_function	1
protein binding	1
cellular anatomical structure	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
lysosome	1
vacuolar lumen	1

Protein interactions and networks

STRING

736 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TCN2	CD320	Q9NPF0	951
TCN2	CBL	P22681	888
TCN2	LTF	P02788	840
TCN2	LMBRD1	Q9NUN5	825
TCN2	MMUT	P22033	806
TCN2	DHFR2	Q86XF0	791
TCN2	MTRR	Q9UBK8	788
TCN2	DHFR	P00374	787
TCN2	MTR	Q99707	785
TCN2	AMN	Q9BXJ7	765
TCN2	MTHFR	P42898	761
TCN2	CUBN	O60494	706
TCN2	AK1	P00568	702
TCN2	BHMT	Q93088	666
TCN2	SLC19A1	P41440	652

IntAct

17 interactions, top by confidence:

A	B	Type	Score
TCN2	CD320	psi-mi:“MI:0407”(direct interaction)	0.680
PAXIP1	TCN2	psi-mi:“MI:0915”(physical association)	0.370
TCN2	HSPA5	psi-mi:“MI:0914”(association)	0.350
TCN2	CLTCL1	psi-mi:“MI:0914”(association)	0.350
TCN2		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (15): TCN2 (Affinity Capture-MS), TCN2 (Reconstituted Complex), HSPA5 (Affinity Capture-MS), DNAJC3 (Affinity Capture-MS), INTS12 (Affinity Capture-MS), INTS1 (Affinity Capture-MS), CLTCL1 (Affinity Capture-MS), POGLUT1 (Affinity Capture-MS), TCN2 (Affinity Capture-MS), TCN2 (Affinity Capture-MS), NQO1 (Cross-Linking-MS (XL-MS)), TCN2 (Protein-peptide), TCN2 (Reconstituted Complex), APP (Reconstituted Complex), TCN2 (Two-hybrid)

ESM2 similar proteins: A4D0V7, A6H684, A6NDA9, A6NFU0, A7E3C4, D3ZNQ3, E7FBY6, F1LW30, F1QVU0, F8VQ03, O95256, P0DV84, P20062, P27931, P97793, Q08BN9, Q0P3U3, Q2NKH9, Q2YDM8, Q3U095, Q52KP5, Q5M7W6, Q5SS91, Q5SY16, Q5U3T0, Q5XI89, Q5XWD5, Q640M6, Q6AXV7, Q6ITT3, Q6P2S7, Q6P3V7, Q6PFC5, Q86VS3, Q8C8H8, Q8CIP5, Q8K1S2, Q8NHY0, Q8VI38, Q8WTR4

Diamond homologs: O88968, P20062, Q5REL7, Q9R0D6, Q9XSC9, P17267, P17630, P20061, P27352, P52787, Q5XWD5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	13
Uncertain significance	248
Likely benign	352
Benign	53

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100	NM_000355.4(TCN2):c.581-176A>T	Pathogenic
1184573	NM_000355.4(TCN2):c.172del (p.Leu58fs)	Pathogenic
1332781	NM_000355.4(TCN2):c.1003C>T (p.Gln335Ter)	Pathogenic
1353281	NM_000355.4(TCN2):c.1106+1G>A	Pathogenic
1395597	NM_000355.4(TCN2):c.882del (p.Val295fs)	Pathogenic
1458198	NC_000022.10:g.(?31003319)(31022508_?)del	Pathogenic
1675884	NM_000355.4(TCN2):c.997dup (p.Thr333fs)	Pathogenic
1810225	NM_000355.4(TCN2):c.1127dup (p.Leu376fs)	Pathogenic
2138436	NM_000355.4(TCN2):c.937C>T (p.Arg313Ter)	Pathogenic
2187312	NM_000355.4(TCN2):c.358_359del (p.Arg120fs)	Pathogenic
2444209	NM_000355.4(TCN2):c.623_624del (p.Arg208fs)	Pathogenic
2699714	NM_000355.4(TCN2):c.494_495del (p.Cys165fs)	Pathogenic
2700602	NM_000355.4(TCN2):c.962dup (p.Thr322fs)	Pathogenic
2707610	NM_000355.4(TCN2):c.380del (p.Leu127fs)	Pathogenic
2725209	NM_000355.4(TCN2):c.324C>A (p.Tyr108Ter)	Pathogenic
2745766	NM_000355.4(TCN2):c.632dup (p.Asn212fs)	Pathogenic
2750346	NM_000355.4(TCN2):c.649_650del (p.Gln217fs)	Pathogenic
2805322	NM_000355.4(TCN2):c.117dup (p.Pro40fs)	Pathogenic
2810295	NM_000355.4(TCN2):c.420_421del (p.Arg140fs)	Pathogenic
2812675	NM_000355.4(TCN2):c.1090G>T (p.Glu364Ter)	Pathogenic
2838618	NM_000355.4(TCN2):c.964dup (p.Thr322fs)	Pathogenic
2844837	NM_000355.4(TCN2):c.463dup (p.Tyr155fs)	Pathogenic
2851360	NM_000355.4(TCN2):c.134_155del (p.Leu45fs)	Pathogenic
2891030	NM_000355.4(TCN2):c.466C>T (p.Gln156Ter)	Pathogenic
2897024	NM_000355.4(TCN2):c.324C>G (p.Tyr108Ter)	Pathogenic
2982426	NM_000355.4(TCN2):c.1033C>T (p.Gln345Ter)	Pathogenic
3247358	NC_000022.10:g.(?31003319)(31003402_?)del	Pathogenic
3247369	NC_000022.10:g.(?31018935)(31019090_?)del	Pathogenic
3247380	NC_000022.10:g.(?31008840)(31019090_?)del	Pathogenic
3247391	NC_000022.10:g.(?31010316)(31013502_?)del	Pathogenic

SpliceAI

1640 predictions. Top by Δscore:

Variant	Effect	Δscore
22:30610868:A:AG	acceptor_gain	1.0000
22:30610869:A:AG	acceptor_gain	1.0000
22:30610870:G:GG	acceptor_gain	1.0000
22:30610870:GAA:G	acceptor_gain	1.0000
22:30611011:G:GT	donor_gain	1.0000
22:30611038:C:G	donor_gain	1.0000
22:30611062:GG:G	donor_gain	1.0000
22:30611063:GG:G	donor_gain	1.0000
22:30612871:A:AC	acceptor_loss	1.0000
22:30612872:G:A	acceptor_loss	1.0000
22:30612872:GGTCT:G	acceptor_gain	1.0000
22:30614347:AG:A	acceptor_gain	1.0000
22:30614348:GG:G	acceptor_gain	1.0000
22:30614498:GTGG:G	donor_gain	1.0000
22:30615293:A:AG	acceptor_gain	1.0000
22:30615294:C:G	acceptor_gain	1.0000
22:30615298:A:AG	acceptor_gain	1.0000
22:30615299:A:G	acceptor_gain	1.0000
22:30615300:G:GG	acceptor_gain	1.0000
22:30615359:T:TA	acceptor_gain	1.0000
22:30615469:TACAG:T	donor_loss	1.0000
22:30615470:ACAG:A	donor_loss	1.0000
22:30615471:CAGGT:C	donor_loss	1.0000
22:30615472:AG:A	donor_loss	1.0000
22:30615473:GG:G	donor_loss	1.0000
22:30615474:G:A	donor_loss	1.0000
22:30615475:T:G	donor_loss	1.0000
22:30617473:GCCCA:G	donor_gain	1.0000
22:30617482:T:G	donor_gain	1.0000
22:30610870:GA:G	acceptor_gain	0.9900

AlphaMissense

2774 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:30623046:G:C	W395C	0.983
22:30623046:G:T	W395C	0.983
22:30623044:T:A	W395R	0.979
22:30623044:T:C	W395R	0.979
22:30617492:T:C	F368S	0.972
22:30613007:T:C	L131P	0.971
22:30623003:T:C	L381S	0.966
22:30610963:A:C	S53R	0.965
22:30610965:C:A	S53R	0.965
22:30610965:C:G	S53R	0.965
22:30623041:T:C	F394L	0.962
22:30623043:C:A	F394L	0.962
22:30623043:C:G	F394L	0.962
22:30610975:G:C	G57R	0.961
22:30614414:T:C	C165R	0.958
22:30615453:A:C	S245R	0.958
22:30615455:C:A	S245R	0.958
22:30615455:C:G	S245R	0.958
22:30614416:T:G	C165W	0.957
22:30615333:T:C	C205R	0.957
22:30610979:T:C	L58P	0.956
22:30615335:T:G	C205W	0.954
22:30611033:T:C	L76P	0.953
22:30617491:T:C	F368L	0.952
22:30617493:C:A	F368L	0.952
22:30617493:C:G	F368L	0.952
22:30623045:G:C	W395S	0.950
22:30610985:T:C	L60P	0.949
22:30613007:T:A	L131H	0.949
22:30610982:G:C	R59P	0.948

dbSNP variants (sampled 300 via entrez): RS1000014714 (22:30624534 G>A), RS1000060777 (22:30624366 G>A), RS1000408766 (22:30623698 A>G), RS1000424468 (22:30612535 A>G), RS1000477757 (22:30624395 C>G,T), RS1000516683 (22:30624544 C>G,T), RS1000712733 (22:30615923 C>G,T), RS1000774385 (22:30616147 C>G,T), RS1000908376 (22:30626805 A>G), RS1000958871 (22:30626934 G>A,C,T), RS1001082362 (22:30623156 A>C,G), RS1001116666 (22:30623232 T>A), RS1001215964 (22:30609666 G>C), RS1001351623 (22:30627325 CTG>C), RS1001412017 (22:30606005 C>A)

Disease associations

OMIM: gene MIM:613441 | disease phenotypes: MIM:275350

GenCC curated gene-disease

Disease	Classification	Inheritance
transcobalamin II deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
transcobalamin II deficiency	Definitive	AR

Mondo (2): transcobalamin II deficiency (MONDO:0010149), pancytopenia (MONDO:0001529)

Orphanet (1): Transcobalamin deficiency (Orphanet:859)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000737	Irritability
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001888	Decreased total lymphocyte count
HP:0001896	Reticulocytopenia
HP:0001903	Anemia
HP:0001919	Acute kidney injury
HP:0001972	Macrocytic anemia
HP:0001980	Megaloblastic bone marrow
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002160	Hyperhomocystinemia
HP:0002240	Hepatomegaly
HP:0002720	Decreased circulating IgA concentration
HP:0002850	Decreased circulating total IgM
HP:0003220	Abnormality of chromosome stability
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004313	Decreased circulating immunoglobulin concentration
HP:0004315	Decreased circulating IgG concentration
HP:0012120	Methylmalonic aciduria
HP:0012133	Erythroid hypoplasia

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST005575_34	Moyamoya disease	8.000000e-10
GCST006585_1260	Blood protein levels	1.000000e-120
GCST007445_41	Factor VIII levels	2.000000e-08
GCST007446_12	vWF levels	5.000000e-18
GCST007446_39	vWF levels	8.000000e-18
GCST007446_69	vWF levels	3.000000e-18
GCST007446_79	vWF levels	6.000000e-19
GCST009030_34	Venous thromboembolism	9.000000e-06
GCST010436_5	Type 2 diabetes	2.000000e-07
GCST90006996_3	Gut microbiota relative abundance (Blautia)	4.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004630	factor VIII measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D010198	Pancytopenia	C15.378.243.875

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression, affects expression	3
beauvericin	affects cotreatment, decreases expression	1
bisphenol A	increases expression	1
methylselenic acid	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
aflatoxin B2	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
enniatins	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Fluoxetine	increases expression	1
Methotrexate	affects metabolic processing	1
Silicon Dioxide	decreases expression	1
Theophylline	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	decreases expression	1
Vitamin B 12	increases uptake, affects binding	1
Zidovudine	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression	1
Lactic Acid	increases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 finite cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B4DC	WG3512	Finite cell line
CVCL_B4E2	WG3707	Finite cell line
CVCL_E1DF	Ubigene THP-1 TCN2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000597	PHASE3	COMPLETED	Multi-Center Trial of Anti-Thymocyte Globulin in Treatment of Aplastic Anemia and Other Hematologic Disorders
NCT00260689	PHASE2	COMPLETED	Three Immunosuppressive Treatment Regimens for Severe Aplastic Anemia
NCT00001398	PHASE1	COMPLETED	Stem Cell Factor Medication for Aplastic Anemia
NCT00001399	PHASE1	COMPLETED	Gene Therapy for the Treatment of Fanconi’s Anemia Type C
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT01187017	PHASE1/PHASE2	COMPLETED	A Pilot Study of Fludarabine Plus Cyclophosphamide in Refractory Severe Aplastic Anemia
NCT01193283	PHASE1/PHASE2	COMPLETED	Cyclophosphamide Plus Cyclosporine in Treatment-Naive Severe Aplastic Anemia
NCT00001214	Not specified	COMPLETED	Collection of Blood From Patients With Pancytopenia
NCT03521947	Not specified	UNKNOWN	Management of Childhood Pancytopenia
NCT05473650	Not specified	UNKNOWN	Spectrum of Hematological Disorders in Pediatrics
NCT06999954	Not specified	RECRUITING	Shwachman-Diamond Syndrome Global Patient Survey and Partnering Platform