rs1157135425
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000355.4(TCN2):c.927_930delTCTG(p.Cys309fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000136 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
TCN2
NM_000355.4 frameshift
NM_000355.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.59
Genes affected
TCN2 (HGNC:11653): (transcobalamin 2) 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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 22-30615770-ACTGT-A is Pathogenic according to our data. Variant chr22-30615770-ACTGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 96.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TCN2 | NM_000355.4 | c.927_930delTCTG | p.Cys309fs | frameshift_variant | 6/9 | ENST00000215838.8 | NP_000346.2 | |
TCN2 | NM_001184726.2 | c.846_849delTCTG | p.Cys282fs | frameshift_variant | 6/9 | NP_001171655.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TCN2 | ENST00000215838.8 | c.927_930delTCTG | p.Cys309fs | frameshift_variant | 6/9 | 1 | NM_000355.4 | ENSP00000215838.3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461886Hom.: 0 AF XY: 0.0000124 AC XY: 9AN XY: 727246
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74328
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Transcobalamin II deficiency Pathogenic:2Other:1
not provided, no classification provided | not provided | Inserm U 954, Faculté de Médecine de Nancy | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2023 | This sequence change creates a premature translational stop signal (p.Cys309Trpfs*50) in the TCN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCN2 are known to be pathogenic (PMID: 7980584, 20352340). This variant is present in population databases (rs796064506, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with suspected primary immunodeficiency and/or transcobalamin II deficiency (PMID: 7849710, 32888943). ClinVar contains an entry for this variant (Variation ID: 96). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at