Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2
The NM_025265.4(TSEN2):c.-18+1G>T variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00687 in 152,330 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
TSEN2 (HGNC:28422): (tRNA splicing endonuclease subunit 2) This gene encodes one of the subunits of the tRNA splicing endonuclease. This endonuclease catalyzes the first step in RNA splicing which is the removal of introns. Mutations in this gene have been associated with pontocerebellar hypoplasia type 2. A pseudogene has been identified on chromosome 4. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2009]
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.9, offset of -32, new splice context is: cggGTgtgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
BP6
Variant 3-12484881-G-T is Benign according to our data. Variant chr3-12484881-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 517053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00687 (1047/152330) while in subpopulation AFR AF= 0.0238 (989/41584). AF 95% confidence interval is 0.0226. There are 5 homozygotes in gnomad4. There are 498 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Mar 18, 2021
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -