rs766665967
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_000548.5(TSC2):c.4719G>A(p.Glu1573=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,736 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
TSC2
NM_000548.5 synonymous
NM_000548.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.275
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 -17 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
?
Variant 16-2086249-G-A is Benign according to our data. Variant chr16-2086249-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 536068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=0.275 with no splicing effect.
BS2
?
High AC in GnomAdExome4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.4719G>A | p.Glu1573= | synonymous_variant | 37/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.4719G>A | p.Glu1573= | synonymous_variant | 37/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000360 AC: 9AN: 249982Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135670
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GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460528Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726558
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74360
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tuberous sclerosis 2 Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | May 14, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 12, 2018 | 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. - |
Tuberous sclerosis syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | - - |
Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Dec 05, 2022 | This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.006% [1/15286]; https://gnomad.broadinstitute.org/variant/16-2086249-G-A?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID: 536068). Evolutionary conservation and computational prediction tools for this variant are limited or unavailable. Of note, this is a silent variant and does not change the amino acid, reducing the probability that this variant is disease-causing. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 15, 2021 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at