Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000548.5(TSC2):c.1281C>A(p.Ile427=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,611,964 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I427I) has been classified as Likely benign.
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]
Computational evidence support a benign effect (BayesDel_noAF=-0.53).
BP6
Variant 16-2062520-C-A is Benign according to our data. Variant chr16-2062520-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 49685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2062520-C-A is described in Lovd as [Likely_benign]. Variant chr16-2062520-C-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.178 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00191 (291/152352) while in subpopulation NFE AF= 0.00332 (226/68030). AF 95% confidence interval is 0.00297. There are 2 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Likely benign, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Sep 12, 2022
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Likely benign, no assertion criteria provided
clinical testing
Clinical Genetics, Academic Medical Center
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Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Jul 01, 2024
TSC2: BP4, BP7, BS1 -
Likely benign, no assertion criteria provided
clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
-
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Likely benign, no assertion criteria provided
clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center
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Benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Aug 23, 2016
Variant summary: The c.1281C>A (p.Ile427=) in TSC2 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.0022 (201/93004 chrs tested), predominantly in individuals of European descent (0.0032; 161/50172). This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000068). The variant of interest has been cited as Benign/Likely Benign by multiple reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -
Benign, criteria provided, single submitter
clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Jul 13, 2016
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not specified Benign:6
Benign, criteria provided, single submitter
clinical testing
GeneDx
Oct 23, 2013
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Aug 28, 2015
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Benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
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Benign, no assertion criteria provided
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
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Likely benign, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Dec 08, 2014
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Benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Dec 03, 2021
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Tuberous sclerosis 2 Benign:4
Benign, criteria provided, single submitter
clinical testing
Athena Diagnostics
May 30, 2017
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Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Nov 07, 2021
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Benign, criteria provided, single submitter
clinical testing
Invitae
Feb 01, 2024
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Benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Sep 20, 2022
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Tuberous sclerosis syndrome Benign:2Other:1
not provided, no classification provided
curation
Tuberous sclerosis database (TSC2)
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Benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jan 13, 2018
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Feb 05, 2024
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Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 02, 2014
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
Mar 12, 2021
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Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Benign:1
Likely benign, criteria provided, single submitter