rs35896166

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001406698.1(TSC2):c.-60C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00135 in 1,613,734 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 11 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 16 hom. )

Consequence

TSC2
NM_001406698.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 3.98

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 16-2064371-C-T is Benign according to our data. Variant chr16-2064371-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 65170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2064371-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00695 (1059/152336) while in subpopulation AFR AF= 0.0238 (990/41576). AF 95% confidence interval is 0.0226. There are 11 homozygotes in gnomad4. There are 494 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1059 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.1543C>T	p.Leu515Leu	synonymous_variant	Exon 15 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.1543C>T	p.Leu515Leu	synonymous_variant	Exon 15 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.00693

AC:

1055

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0238

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00198

AC:

498

AN:

251180

Hom.:

AF XY:

0.00139

AC XY:

189

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.0261

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000881

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000762

AC:

1113

AN:

1461398

Hom.:

Cov.:

AF XY:

0.000667

AC XY:

485

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.0266

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.000880

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.00161

GnomAD4 genome

AF:

0.00695

AC:

1059

AN:

152336

Hom.:

Cov.:

AF XY:

0.00663

AC XY:

494

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0238

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00348

Hom.:

Bravo

AF:

0.00832

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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 14, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

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

- -

Jun 07, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

Sep 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.1543C>T (p.Leu515Leu) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 293/121028 control chromosomes (3 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0263918 (274/10382). This frequency is about 384 times the estimated maximal expected allele frequency of a pathogenic TSC2 variant (0.0000688), indicating this is a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Jul 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis 2

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome

Benign:2Other:1

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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

Benign:1

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Oct 30, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.74

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

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