rs137854071
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000548.5(TSC2):c.2071del(p.Arg691AlafsTer7) variant causes a frameshift change involving the alteration of a non-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. F690F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
TSC2
NM_000548.5 frameshift
NM_000548.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.473
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 18 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 16-2071906-TC-T is Pathogenic according to our data. Variant chr16-2071906-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 49715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071906-TC-T is described in Lovd as [Likely_pathogenic]. Variant chr16-2071906-TC-T is described in Lovd as [Pathogenic]. Variant chr16-2071906-TC-T is described in Lovd as [Pathogenic]. Variant chr16-2071906-TC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.2071del | p.Arg691AlafsTer7 | frameshift_variant | 19/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.2071del | p.Arg691AlafsTer7 | frameshift_variant | 19/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tuberous sclerosis 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 12, 2021 | This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg691Alafs*7) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 9463313, 28968464). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49715). This variant is also known as del1bp, 690PheFSr697X. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 05, 2018 | c.2071delC: p.Arg691AlafsX7 in exon 19 in the TSC2 gene (NM_000548.3). The normal sequence with the base(s) that are deleted in braces is: CTTC{C}GCGT. The c.2071delC pathogenic variant in the TSC2 gene has been reported previously in association with tuberous sclerosis complex (Au et al., 1998; Ali et al., 2005; TSC2 LOVD). The deletion causes a frameshift starting with codon Arginine 691, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 7 of the new reading frame, denoted p.Arg691AlafsX7. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the c.2071delCvariant is not observed in large population cohorts (Lek et al., 2016). Therefore, the presence of c.2071delC is consistent with the diagnosis of tuberous sclerosis complex in this individual. - |
Tuberous sclerosis syndrome Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC2) | - | - - |
Computational scores
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Splicing
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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