Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_025265.4(TSEN2):c.960+1_960+5delGTAAG variant causes a splice donor, splice region, intron change. The variant allele was found at a frequency of 0.00000496 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
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]
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.036480688 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-12516658-GAAGGT-G is Pathogenic according to our data. Variant chr3-12516658-GAAGGT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Pontoneocerebellar hypoplasia Pathogenic:1
Mar 09, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: TSEN2 c.960+1_960+5delGTAAG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251408 control chromosomes. c.960+1_960+5delGTAAG has been reported as a compound heterozygous genotype in the literature in two siblings affected with Pontocerebellar Hypoplasia, Type 2B (Namavar_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -