rs778381859
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1PM2PP5_Very_StrongBS1_Supporting
The NM_000355.4(TCN2):c.497_498delTC(p.Leu166ProfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000355.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000119 AC: 30AN: 251426Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135900
GnomAD4 exome AF: 0.000309 AC: 451AN: 1461884Hom.: 0 AF XY: 0.000272 AC XY: 198AN XY: 727246
GnomAD4 genome AF: 0.000158 AC: 24AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74336
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30041674, 20352340, 24305960, 32841161) -
Transcobalamin II deficiency Pathogenic:3
TCN2 NM_000355.3 exon 4 p.Leu166Profs*7 (c.497_498del): This variant has been reported in the literature in at least 4 individuals with Transcobalamin II Deficiency; 3 of these individuals were homozygous, 1 was a compound heterozygote who was identified to have an additional likely disease causing variant in the TCN2 gene (Schiff 2010 PMID:20352340, Trakadis 2014 PMID:24305960). This variant is present in 0.2% (7/24962) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/22-31010402-GTC-G). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or Likely Pathogenic (Variation ID:376919). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a deletion of 2 nucleotides at position 497 which results in a premature stop codon 7 amino acids downstream from this location which is predicted to result in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Li 1994 PMID:7980584). In summary, this variant is classified as pathogenic. -
The TCN2 c.497_498delTC (p.Leu166ProfsTer7) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Leu166ProfsTer7 variant has been reported in two studies and is found in a total of four unrelated individuals with transcobalamin II deficiency, including in three in a homozygous state and in one in a compound heterozygous state (Schiff et al. 2010; Trakadis et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00048 in the African population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of frameshift variants, the p.Leu166ProfsTer7 variant is classified as likely pathogenic for transcobalamin II deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
This sequence change creates a premature translational stop signal (p.Leu166Profs*7) 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 (rs778381859, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with transcobalamin deficiency (PMID: 20352340). For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Uncertain:1
Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at