chr16-2055399-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000548.5(TSC2):c.482-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0951 in 1,613,492 control chromosomes in the GnomAD database, including 8,382 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1381 hom., cov: 32)

Exomes 𝑓: 0.092 ( 7001 hom. )

Consequence

TSC2
NM_000548.5 splice_region, intron

Scores

Splicing: ADA: 0.0006049

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17O:3

Conservation

PhyloP100: 0.111

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 16-2055399-C-T is Benign according to our data. Variant chr16-2055399-C-T is described in ClinVar as [Benign]. Clinvar id is 49957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055399-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.482-3C>T		splice_region_variant, intron_variant	Intron 5 of 41	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.482-3C>T		splice_region_variant, intron_variant	Intron 5 of 41	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

18710

AN:

152068

Hom.:

1375

Cov.:

show subpopulations

Gnomad AFR

AF:

0.197

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.0949

Gnomad ASJ

AF:

0.146

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0280

Gnomad FIN

AF:

0.135

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.0974

Gnomad OTH

AF:

0.127

GnomAD3 exomes

AF:

0.0868

AC:

21836

AN:

251444

Hom.:

1315

AF XY:

0.0840

AC XY:

11413

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.200

Gnomad AMR exome

AF:

0.0571

Gnomad ASJ exome

AF:

0.138

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0259

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.0966

Gnomad OTH exome

AF:

0.105

GnomAD4 exome

AF:

0.0922

AC:

134667

AN:

1461306

Hom.:

7001

Cov.:

AF XY:

0.0898

AC XY:

65260

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.203

Gnomad4 AMR exome

AF:

0.0622

Gnomad4 ASJ exome

AF:

0.140

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0291

Gnomad4 FIN exome

AF:

0.126

Gnomad4 NFE exome

AF:

0.0950

Gnomad4 OTH exome

AF:

0.0962

GnomAD4 genome

AF:

0.123

AC:

18740

AN:

152186

Hom.:

1381

Cov.:

AF XY:

0.122

AC XY:

9081

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.198

Gnomad4 AMR

AF:

0.0947

Gnomad4 ASJ

AF:

0.146

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0278

Gnomad4 FIN

AF:

0.135

Gnomad4 NFE

AF:

0.0974

Gnomad4 OTH

AF:

0.125

Alfa

AF:

0.111

Hom.:

1447

Bravo

AF:

0.125

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.106

EpiControl

AF:

0.107

ClinVar

Significance: Benign

Submissions summary: Benign:17Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	482-3C>T in intron 5 of TSC2: This variant is not expected to have clinical sign ificance because it has been identified in 19.1% (838/4396) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs1800720). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Tuberous sclerosis 2

Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 23, 2016	Variant summary: c.482-3C>T in TSC2 gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing pattern, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.087 (10574/121392 chrs tested), predominantly in individuals of African descent (0.2; 2098/10406 chrs tested) including numerous homozygous occurrences. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.00006 suggesting that it is a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but cited as Benign/ Likely Benign by multiple reputable databases/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Tuberous sclerosis syndrome

Benign:1Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2014

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

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

- -

Neoplasm of brain

Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.6

DANN

Benign

0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00060

dbscSNV1_RF

Benign

0.074

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