rs137854273
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000548.5(TSC2):โc.4207delโ(p.Asp1403ThrfsTer8) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (โ ). Synonymous variant affecting the same amino acid position (i.e. G1402G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 34)
Exomes ๐: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TSC2
NM_000548.5 frameshift
NM_000548.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.48
Genes affected
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-2084425-TG-T is Pathogenic according to our data. Variant chr16-2084425-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 49287.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2084425-TG-T is described in Lovd as [Pathogenic]. Variant chr16-2084425-TG-T is described in Lovd as [Pathogenic]. Variant chr16-2084425-TG-T is described in Lovd as [Pathogenic]. Variant chr16-2084425-TG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.4207del | p.Asp1403ThrfsTer8 | frameshift_variant | 34/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.4207del | p.Asp1403ThrfsTer8 | frameshift_variant | 34/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1458826Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 725622
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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1458826
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33
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0
AN XY:
725622
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2015 | The c.4207delG deletion in the TSC2 gene has been reported previously multiple times inassociation with tuberous sclerosis complex (TSC) (Niida et al., 2001; TSC2 LOVD). The deletion causes a frameshift starting withcodon Aspartic acid 1403, changes this amino acid to a Threonine residue and creates apremature Stop codon at position 8 of the new reading frame, denoted p.Asp1403ThrfsX8.This variant is predicted to cause loss of normal protein function either through proteintruncation or nonsense-mediated mRNA decay. Therefore, we interpret c.4207delG as a pathogenic variant. - |
Tuberous sclerosis syndrome Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC2) | - | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at