rs1157135425
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The ENST00000215838.8(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
Consequence
ENST00000215838.8 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TCN2 | NM_000355.4 | c.927_930del | p.Cys309TrpfsTer50 | frameshift_variant | 6/9 | ENST00000215838.8 | NP_000346.2 | |
TCN2 | NM_001184726.2 | c.846_849del | p.Cys282TrpfsTer50 | 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_930del | p.Cys309TrpfsTer50 | frameshift_variant | 6/9 | 1 | NM_000355.4 | ENSP00000215838 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461886Hom.: 0 AF XY: 0.0000124 AC XY: 9AN XY: 727246
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74328
ClinVar
Submissions by phenotype
Transcobalamin II deficiency Pathogenic:2Other:1
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. - |
not provided, no classification provided | not provided | Inserm U 954, Faculté de Médecine de Nancy | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at