rs1157135425
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000355.4(TCN2):c.927_930del(p.Cys309TrpfsTer50) 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 (★). Synonymous variant affecting the same amino acid position (i.e. D308D) has been classified as Likely benign. 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]
Genome browser will be placed here
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 | UniProt |
---|---|---|---|---|---|---|---|
TCN2 | NM_000355.4 | c.927_930del | p.Cys309TrpfsTer50 | frameshift_variant | 6/9 | ENST00000215838.8 | |
TCN2 | NM_001184726.2 | c.846_849del | p.Cys282TrpfsTer50 | frameshift_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TCN2 | ENST00000215838.8 | c.927_930del | p.Cys309TrpfsTer50 | frameshift_variant | 6/9 | 1 | NM_000355.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
3
AN:
152144
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461886Hom.: 0 AF XY: 0.0000124 AC XY: 9AN XY: 727246
GnomAD4 exome
AF:
AC:
19
AN:
1461886
Hom.:
AF XY:
AC XY:
9
AN XY:
727246
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74328
GnomAD4 genome
?
AF:
AC:
3
AN:
152144
Hom.:
Cov.:
33
AF XY:
AC XY:
2
AN XY:
74328
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
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, criteria provided, single submitter | clinical testing | Invitae | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2009 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at