rs587778732

Variant names:

• chr16-2082467-CTGCCAAGGA-G
• rs587778732
• NM_000548.5:c.3846_3855delCTGCCAAGGAinsG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM4 BP6

The NM_000548.5(TSC2):​c.3846_3855delCTGCCAAGGAinsG​(p.Ser1282_Gly1285delinsArg) variant causes a missense, conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. 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 missense, conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8 O:1
• Conservation: PhyloP100: 5.83
• Publications: 1 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000548.5.
• 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 VariationId is 135377.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3846_3855delCTGCCAAGGAinsG	p.Ser1282_Gly1285delinsArg	missense_variant, conservative_inframe_deletion	Exon 32 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3846_3855delCTGCCAAGGAinsG	p.Ser1282_Gly1285delinsArg	missense_variant, conservative_inframe_deletion	Exon 32 of 42	5	NM_000548.5	ENSP00000219476.3

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:5 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1 Benign:3

Jan 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 21, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Uncertain:2 Benign:1

Sep 15, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1 Other:1

Dec 21, 2016

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TSC2 c.3846_3855delinsG (p.Ser1282_Gly1285delinsArg) results in an in-frame deletion-insertion that is predicted to delete/insert 4 amino acids from the protein and also cause changes in 1 amino acid. The variant allele was found at a frequency of 0.00013 in 281462 control chromosomes. The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), strongly suggesting that the variant is benign. c.3846_3855delinsG has been reported in the literature in unspecified individual(s) affected with epilepsy and neurodevelopmental disorder (Lindy_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Tuberous Sclerosis Complex. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 135377). Based on the evidence outlined above, the variant was classified as likely benign. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Uncertain:1

Jun 01, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Benign:1

Apr 08, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 14, 2022

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). -

Hereditary cancer-predisposing syndrome Benign:1

Aug 16, 2023

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=37/163	disease causing

Splicing

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

Other links and lift over

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