16-2088268-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000548.5(TSC2):c.5202T>C(p.Asp1734Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,586,204 control chromosomes in the GnomAD database, including 38,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10451 hom., cov: 32)

Exomes 𝑓: 0.18 ( 28473 hom. )

Consequence

TSC2
NM_000548.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19O:2

Conservation

PhyloP100: 0.915

Publications

32 publications found

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 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

TSC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 16-2088268-T-C is Benign according to our data. Variant chr16-2088268-T-C is described in ClinVar as Benign. ClinVar VariationId is 49895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.915 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.5202T>C	p.Asp1734Asp	synonymous_variant	Exon 41 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.5202T>C	p.Asp1734Asp	synonymous_variant	Exon 41 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.345

AC:

45504

AN:

131840

Hom.:

10415

Cov.:

show subpopulations

Gnomad AFR

AF:

0.674

Gnomad AMI

AF:

0.233

Gnomad AMR

AF:

0.229

Gnomad ASJ

AF:

0.227

Gnomad EAS

AF:

0.00166

Gnomad SAS

AF:

0.0944

Gnomad FIN

AF:

0.233

Gnomad MID

AF:

0.257

Gnomad NFE

AF:

0.209

Gnomad OTH

AF:

0.298

GnomAD2 exomes

AF:

0.178

AC:

44601

AN:

249878

AF XY:

0.169

show subpopulations

Gnomad AFR exome

AF:

0.658

Gnomad AMR exome

AF:

0.113

Gnomad ASJ exome

AF:

0.209

Gnomad EAS exome

AF:

0.000388

Gnomad FIN exome

AF:

0.207

Gnomad NFE exome

AF:

0.177

Gnomad OTH exome

AF:

0.176

GnomAD4 exome

AF:

0.179

AC:

259701

AN:

1454234

Hom.:

28473

Cov.:

AF XY:

0.174

AC XY:

126080

AN XY:

723304

show subpopulations

African (AFR)

AF:

0.661

AC:

22125

AN:

33462

American (AMR)

AF:

0.123

AC:

5440

AN:

44160

Ashkenazi Jewish (ASJ)

AF:

0.209

AC:

5445

AN:

26076

East Asian (EAS)

AF:

0.000349

AC:

AN:

37302

South Asian (SAS)

AF:

0.0830

AC:

7119

AN:

85724

European-Finnish (FIN)

AF:

0.206

AC:

10716

AN:

52104

Middle Eastern (MID)

AF:

0.189

AC:

1089

AN:

5754

European-Non Finnish (NFE)

AF:

0.177

AC:

195945

AN:

1109456

Other (OTH)

AF:

0.196

AC:

11809

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

14307

28615

42922

57230

71537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7014

14028

21042

28056

35070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.346

AC:

45598

AN:

131970

Hom.:

10451

Cov.:

AF XY:

0.338

AC XY:

21867

AN XY:

64624

show subpopulations

African (AFR)

AF:

0.674

AC:

26810

AN:

39782

American (AMR)

AF:

0.229

AC:

3003

AN:

13096

Ashkenazi Jewish (ASJ)

AF:

0.227

AC:

671

AN:

2960

East Asian (EAS)

AF:

0.00166

AC:

AN:

3610

South Asian (SAS)

AF:

0.0941

AC:

375

AN:

3984

European-Finnish (FIN)

AF:

0.233

AC:

2179

AN:

9350

Middle Eastern (MID)

AF:

0.248

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.209

AC:

11814

AN:

56500

Other (OTH)

AF:

0.294

AC:

531

AN:

1806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1255

2510

3765

5020

6275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

394

788

1182

1576

1970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.205

Hom.:

8412

Bravo

AF:

0.315

EpiCase

AF:

0.179

EpiControl

AF:

0.170

ClinVar

Significance: Benign

Submissions summary: Benign:19Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 30% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 28. Only high quality variants are reported. -

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. -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Asp1734Asp in exon 41 of TSC2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 36.6% (1607/4396) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1748). -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Tuberous sclerosis 2

Benign:4

Jun 06, 2025

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

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

- -

not provided

Benign:4

Mar 03, 2015

GeneDx

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.5202T>C (p.Asp1734Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 22671/120414 control chromosomes (3647 homozygotes) at a frequency of 0.1882754, which is approximately 2738 times the estimated maximal expected allele frequency of a pathogenic TSC2 variant (0.0000688), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tuberous sclerosis syndrome

Benign:3Other:1

Jan 12, 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. -

Tuberous sclerosis database (TSC2)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

Mar 28, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease, adult type

Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Nov 20, 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. -

Tuberous sclerosis syndrome;C0751674: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

-0.65

CADD

Benign

6.8

(source)

DANN

Benign

0.81

PhyloP100

0.92

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over