Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2
The NM_000548.5(TSC2):c.4107G>A(p.Arg1369Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,612,694 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1369R) 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]
TSC2 Gene-Disease associations (from GenCC):
tuberous sclerosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
tuberous sclerosis 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
lymphangioleiomyomatosis
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
tuberous sclerosis complex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Our verdict: Benign. The variant received -15 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
Variant 16-2084329-G-A is Benign according to our data. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084329-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 207681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=1.17 with no splicing effect.
This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
not specifiedBenign:1
Nov 22, 2014
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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. -
Tuberous sclerosis syndromeBenign:1
Feb 05, 2024
All of Us Research Program, National Institutes of Health
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
TSC2-related disorderBenign:1
Jul 12, 2023
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not providedBenign:1
Oct 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
TSC2: BP4, BP7 -
Hereditary cancer-predisposing syndromeBenign:1
Apr 10, 2019
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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. -