rs45517150
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000548.5(TSC2):c.976-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
TSC2
NM_000548.5 intron
NM_000548.5 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.05
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 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-2060655-G-A is Pathogenic according to our data. Variant chr16-2060655-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 49396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2060655-G-A is described in Lovd as [Pathogenic]. Variant chr16-2060655-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TSC2 | NM_000548.5 | c.976-15G>A | intron_variant | ENST00000219476.9 | NP_000539.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TSC2 | ENST00000219476.9 | c.976-15G>A | intron_variant | 5 | NM_000548.5 | ENSP00000219476.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tuberous sclerosis 2 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University | Aug 01, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 22, 2023 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 11 (referred to as exon 10), but is expected to preserve the integrity of the reading-frame (PMID: 10533066, 11068191). ClinVar contains an entry for this variant (Variation ID: 49396). This variant is also known as IVS9-15G>A. This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 10533066, 11112665, 21520333, 26540169). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 10 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Intronic variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 11068191, 10533066).The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 26540169, 11112665, PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 26, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Sep 23, 2022 | This variant has been reported in more than 10 individuals with a clinical diagnosis or suspicion of tuberous sclerosis, including as de novo in at least one individual and in the mosaic state in another (Selected publications: Mayer 1999 PMID: 10533066; Dabora 2001 PMID: 11112665; Tyburczy 2015 PMID: 26540169; Wang 2021 PMID: 33278787). This variant is absent from large control databases but is present in ClinVar, with multiple laboratories classifying it as pathogenic (Variation ID: 49396). Transcriptional analyses demonstrated that this variant leads to two abnormal transcripts: one with the in-frame skipping of exon 11, and one with the activation of a cryptic splice acceptor in exon 11 that results in the deletion of 56 nucleotides, introducing a frameshift and premature stop codon (Mayer 1999 PMID: 10533066; Mayer 2000 PMID: 11068191). Loss of function variants are a known mechanism of disease for this gene (Rosset 2017 PMID: 28222202). In summary, this variant is classified as pathogenic. - |
TSC2-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 08, 2023 | The TSC2 c.976-15G>A variant is predicted to interfere with splicing. In the literature this variant is also referred to as IVS9-15G>A. Based on available splicing prediction programs (Alamut Visual Plus v1.6.1), this variant creates a cryptic splice acceptor site. Functional studies have also shown that this variant leads to skipping of exon 10 and the creation of a cryptic splice acceptor in exon 10 (Mayer et al. 1999. PubMed ID: 10533066; Mayer et al. 2000. PubMed ID: 11068191). This variant has been reported in individuals with tuberous sclerosis complex (TSC) (Mayer et al. 1999. PubMed ID: 10533066; Dabora et al. 2000. PubMed ID: 11112665; Mayer et al. 2000. PubMed ID: 11068191; Tyburczy et al. 2015. PubMed ID: 26540169; Rosset et al. 2017. PubMed ID: 28968464). This variant has also been reported in TSC patients in the presumed mosaic state (allelic frequency <50%) (Tyburczy et al. 2015. PubMed ID: 26540169). This variant has also been reported in an individual with status epilepticus (Wang et al. 2020. PubMed ID: 33278787). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is interpreted as pathogenic in ClinVar by multiple clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/49396/). This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 19, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In vitro mRNA analysis indicates the c.976-15G>A variant leads aberrant splicing of exon 11 (Mayer et al., 2000); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 10533066, 11112665, 26540169, 17304050, 19369101, 28968464, 33278787, 18466115, 11068191) - |
Tuberous sclerosis syndrome Other:1
| not provided, no classification provided | curation | Tuberous sclerosis database (TSC2) | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
DS_AL_spliceai
Position offset: 15
Find out detailed SpliceAI scores and Pangolin per-transcript scores at