Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_ModeratePM2PP3PP5_Moderate
The NM_000548.5(TSC2):c.3641_3814+28del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. N1214N) has been classified as Likely benign.
TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
?
PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.037426252 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 16-2081624-AACCCGCTCAGCCCTTTCTCCTCGGACATCAACAACATGCCCCTGCAGGAGCTGTCTAACGCCCTCATGGCGGCTGAGCGCTTCAAGGAGCACCGGGACACAGCCCTGTACAAGTCACTGTCGGTGCCGGCAGCCAGCACGGCCAAACCCCCTCCTCTGCCTCGCTCCAACACAGGTGAGTGGCATGGCGGGCCTTGGCACGG-A is Pathogenic according to our data. Variant chr16-2081624-AACCCGCTCAGCCCTTTCTCCTCGGACATCAACAACATGCCCCTGCAGGAGCTGTCTAACGCCCTCATGGCGGCTGAGCGCTTCAAGGAGCACCGGGACACAGCCCTGTACAAGTCACTGTCGGTGCCGGCAGCCAGCACGGCCAAACCCCCTCCTCTGCCTCGCTCCAACACAGGTGAGTGGCATGGCGGGCCTTGGCACGG-A is described in ClinVar as [Pathogenic]. Clinvar id is 535979.Status of the report is criteria_provided_single_submitter, 1 stars.
This variant is a gross deletion of the genomic region encompassing part of exon 31 of the TSC2 gene including the exon 31-intron 31 boundary (c.3641_3814+28del). This is expected to create a premature translational stop signal and result in an absent or disrupted protein product. Similar deletions have not been reported in the literature in individuals with TSC2-related disease. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). For these reasons, this variant has been classified as Pathogenic. -