rs1555895066
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000355.4(TCN2):c.766dup(p.Ser256PhefsTer48) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
TCN2
NM_000355.4 frameshift
NM_000355.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.876
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 18 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 22-30615611-C-CT is Pathogenic according to our data. Variant chr22-30615611-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 460319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TCN2 | NM_000355.4 | c.766dup | p.Ser256PhefsTer48 | frameshift_variant | 6/9 | ENST00000215838.8 | |
TCN2 | NM_001184726.2 | c.685dup | p.Ser229PhefsTer48 | frameshift_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TCN2 | ENST00000215838.8 | c.766dup | p.Ser256PhefsTer48 | frameshift_variant | 6/9 | 1 | NM_000355.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 57
GnomAD4 exome
Cov.:
57
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Transcobalamin II deficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 28, 2017 | This sequence change creates a premature translational stop signal (p.Ser256Phefs*48) in the TCN2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TCN2-related disease. Loss-of-function variants in TCN2 are known to be pathogenic (PMID: 7980584, 20352340). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 14, 2020 | - - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at