rs201599540
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Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2
The NM_000548.5(TSC2):c.3768G>A(p.Pro1256=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,612,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000044 ( 0 hom. )
Consequence
TSC2
NM_000548.5 synonymous
NM_000548.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.23
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 Benign. Variant got -10 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
?
Variant 16-2081752-G-A is Benign according to our data. Variant chr16-2081752-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281623.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2, Benign=1}. Variant chr16-2081752-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-2.23 with no splicing effect.
BS2
?
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.3768G>A | p.Pro1256= | synonymous_variant | 31/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.3768G>A | p.Pro1256= | synonymous_variant | 31/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152226Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000320 AC: 8AN: 249690Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135586
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GnomAD4 exome AF: 0.0000438 AC: 64AN: 1460480Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 39AN XY: 726534
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GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152344Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74504
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 30, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 09, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 16, 2016 | - - |
Tuberous sclerosis 2 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 03, 2017 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 16, 2020 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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