rs587778732

chr16-2082466-GCTGCCAAGGA-GG

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000548.5(TSC2):c.3846_3855delinsG(p.Ser1282_Gly1285delinsArg) variant causes a protein altering change. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1282S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 protein_altering
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7 O:1
• Conservation: PhyloP100: 5.83

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 16-2082467-CTGCCAAGGA-G is Benign according to our data. Variant chr16-2082467-CTGCCAAGGA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135377.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=4, not_provided=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.3846_3855delinsG	p.Ser1282_Gly1285delinsArg	protein_altering_variant	32/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.3846_3855delinsG	p.Ser1282_Gly1285delinsArg	protein_altering_variant	32/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 21, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 13, 2023	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 17, 2019	The TSC2 c.3846_3855delinsG (p.Ser1282_Gly1285delinsArg) variant has been reported in the published literature in individuals with epilepsy and/or neurodevelopmental delay (PMID: 29655203 (2018)) and in an infant who fulfils the diagnostic criteria for Tuberous sclerosis complex (TSC) (PMID: 26703369 (2016)). The infant was reported to have an additional pathogenic variant in TSC2, suggesting the c.3846_3855delinsG variant may not be responsible for disease (PMID: 26703369 (2016)). An experimental study describes this variant as having no impact on TSC2 function (PMID: 26703369 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2016	- -

not specified Uncertain:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 21, 2016	- -

Tuberous sclerosis syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Apr 08, 2021

The TSC2 c.3846_3855delinsG (p.Ser1282_Gly1285delinsArg) change is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). This change is predicted to delete four amino acids and replace them with an arginine while preserving the reading frame. Functional studies indicate that this variant does not affect TSC2 protein stability, the interaction between TSC1 and TSC2, or TSC complex-dependent inhibition of TORC1 activity (BS3; PMID: 26703369). This variant has been identified in a family who fulfills diagnostic criteria for TSC and also carries a definite TSC-causing variant (BP2; PMID: 26703369), as well as unaffected individuals (internal data). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS3, BP2, PM2_Supporting. -

TSC2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 14, 2022

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). -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2023

This alteration is classified as benign based on a combination of the following: 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587778732; hg19: chr16-2132468; COSMIC: COSV105872618; COSMIC: COSV105872618;