rs397515023
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000548.5(TSC2):c.4473delA(p.Val1492CysfsTer84) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000548.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Tuberous sclerosis 2 Pathogenic:2
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While this particular variant has not been reported in the literature, truncating variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). For these reasons, this variant has been classified as Pathogenic. This sequence change deletes 1 nucleotide from exon 34 of the TSC2 mRNA (c.4473delA), causing a frameshift at codon 1492. This creates a premature translational stop signal (p.Val1492Cysfs*84) and is expected to result in an absent or disrupted protein product. -
Lymphangiomyomatosis Pathogenic:1
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
not provided Pathogenic:1
The c.4473delA pathogenic variant in the TSC2 gene has been reported previously in an individual with suspected tuberous sclerosis complex (TSC2 LOVD). The deletion causes a frameshift starting with codon Valine 1492, changes this amino acid to a Cysteine residue and creates a premature Stop codon at position 84 of the new reading frame, denoted p.Val1492CysfsX84. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, it was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at