16-2075833-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000548.5(TSC2):c.2580T>C(p.Phe860Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0786 in 1,612,884 control chromosomes in the GnomAD database, including 5,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 504 hom., cov: 33)

Exomes 𝑓: 0.079 ( 4803 hom. )

Consequence

TSC2
NM_000548.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18O:2

Conservation

PhyloP100: -2.29

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 16-2075833-T-C is Benign according to our data. Variant chr16-2075833-T-C is described in ClinVar as [Benign]. Clinvar id is 49573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2075833-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.29 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.088 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.2580T>C	p.Phe860Phe	synonymous_variant	Exon 23 of 42	ENST00000219476.9	NP_000539.2	P49815-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.2580T>C	p.Phe860Phe	synonymous_variant	Exon 23 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.0781

AC:

11884

AN:

152088

Hom.:

502

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0904

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0553

Gnomad ASJ

AF:

0.0798

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.0607

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0790

Gnomad OTH

AF:

0.0655

GnomAD3 exomes

AF:

0.0697

AC:

17460

AN:

250520

Hom.:

734

AF XY:

0.0707

AC XY:

9597

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.0888

Gnomad AMR exome

AF:

0.0353

Gnomad ASJ exome

AF:

0.0766

Gnomad EAS exome

AF:

0.00142

Gnomad SAS exome

AF:

0.0634

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.0819

Gnomad OTH exome

AF:

0.0694

GnomAD4 exome

AF:

0.0786

AC:

114807

AN:

1460678

Hom.:

4803

Cov.:

AF XY:

0.0778

AC XY:

56567

AN XY:

726662

show subpopulations

Gnomad4 AFR exome

AF:

0.0866

Gnomad4 AMR exome

AF:

0.0363

Gnomad4 ASJ exome

AF:

0.0794

Gnomad4 EAS exome

AF:

0.000579

Gnomad4 SAS exome

AF:

0.0642

Gnomad4 FIN exome

AF:

0.113

Gnomad4 NFE exome

AF:

0.0827

Gnomad4 OTH exome

AF:

0.0730

GnomAD4 genome

AF:

0.0781

AC:

11892

AN:

152206

Hom.:

504

Cov.:

AF XY:

0.0789

AC XY:

5871

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0904

Gnomad4 AMR

AF:

0.0553

Gnomad4 ASJ

AF:

0.0798

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.0603

Gnomad4 FIN

AF:

0.111

Gnomad4 NFE

AF:

0.0790

Gnomad4 OTH

AF:

0.0648

Alfa

AF:

0.0713

Hom.:

318

Bravo

AF:

0.0732

Asia WGS

AF:

0.0370

AC:

127

AN:

3478

EpiCase

AF:

0.0806

EpiControl

AF:

0.0741

ClinVar

Significance: Benign

Submissions summary: Benign:18Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 16, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Phe860Phe in exon 23 of TSC2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 8.7% (381/4396) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs13337626). -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Tuberous sclerosis 2

Benign:4

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 14, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 23, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The TSC2 c.2580T>C (p.Phe860Phe) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predicting no significant impact on splicing and alterations to ESE binding, however, these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 8679/119772 (1/13, 390 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic TSC2 variant of 1/14534, suggesting this variant is likely a benign polymorphism. In addition, multiple reputable clinical laboratories/databases cite the variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tuberous sclerosis syndrome

Benign:3Other:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Hereditary cancer-predisposing syndrome

Benign:1

Nov 19, 2014

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: 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. -

Lymphangiomyomatosis

Other:1

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.079

DANN

Benign

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over