16-2088268-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000548.5(TSC2):c.5202T>C(p.Asp1734=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:2
• Conservation: PhyloP100: 0.915

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 49895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088268-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
TSC2	NM_000548.5	c.5202T>C	p.Asp1734=	synonymous_variant	41/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.5202T>C	p.Asp1734=	synonymous_variant	41/42	5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.345 AC: 45504 AN: 131840 Hom.: 10415 Cov.: 32

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

GnomAD3 exomes AF: 0.178 AC: 44601 AN: 249878 Hom.: 6445 AF XY: 0.169 AC XY: 22884 AN XY: 135454

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 SAS exome AF: 0.0812

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.: 36 AF XY: 0.174 AC XY: 126080 AN XY: 723304

Gnomad4 AFR exome AF: 0.661

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.209

Gnomad4 EAS exome AF: 0.000349

Gnomad4 SAS exome AF: 0.0830

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.177

Gnomad4 OTH exome AF: 0.196

GnomAD4 genome AF: 0.346 AC: 45598 AN: 131970 Hom.: 10451 Cov.: 32 AF XY: 0.338 AC XY: 21867 AN XY: 64624

Gnomad4 AFR AF: 0.674

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.00166

Gnomad4 SAS AF: 0.0941

Gnomad4 FIN AF: 0.233

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.294

Alfa AF: 0.192 Hom.: 4809

Bravo AF: 0.315

EpiCase AF: 0.179

EpiControl AF: 0.170

ClinVar

Significance: Benign

Submissions summary: Benign:15 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Tuberous sclerosis 2 Benign:4

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	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 23, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Tuberous sclerosis syndrome Benign:2 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
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 20, 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)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	6.8
Dann	Benign	0.81

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

Other links and lift over

dbSNP: rs1748; hg19: chr16-2138269; COSMIC: COSV51916353; COSMIC: COSV51916353;