rs34012042

Positions:

• chr16-2064406-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000548.5(TSC2):​c.1578C>T​(p.Ser526Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0624 in 1,613,664 control chromosomes in the GnomAD database, including 3,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (259 hom., cov: 33)
  • Exomes 𝑓: 0.064 (3284 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18 O:3
• Conservation: PhyloP100: 0.0420

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 16-2064406-C-T is Benign according to our data. Variant chr16-2064406-C-T is described in ClinVar as [Benign]. Clinvar id is 49162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2064406-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.042 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1578C>T	p.Ser526Ser	synonymous_variant	15/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1578C>T	p.Ser526Ser	synonymous_variant	15/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 7447 AN: 152232 Hom.: 258 Cov.: 33

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0493

Gnomad ASJ AF: 0.0939

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0683

Gnomad FIN AF: 0.0922

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0641

Gnomad OTH AF: 0.0521

GnomAD3 exomes AF: 0.0571 AC: 14349 AN: 251164 Hom.: 513 AF XY: 0.0597 AC XY: 8102 AN XY: 135816

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.0333

Gnomad ASJ exome AF: 0.0992

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0698

Gnomad FIN exome AF: 0.0863

Gnomad NFE exome AF: 0.0669

Gnomad OTH exome AF: 0.0651

GnomAD4 exome AF: 0.0638 AC: 93238 AN: 1461314 Hom.: 3284 Cov.: 31 AF XY: 0.0640 AC XY: 46536 AN XY: 726942

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.0339

Gnomad4 ASJ exome AF: 0.0997

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0696

Gnomad4 FIN exome AF: 0.0834

Gnomad4 NFE exome AF: 0.0667

Gnomad4 OTH exome AF: 0.0603

GnomAD4 genome AF: 0.0489 AC: 7447 AN: 152350 Hom.: 259 Cov.: 33 AF XY: 0.0503 AC XY: 3746 AN XY: 74504

Gnomad4 AFR AF: 0.0132

Gnomad4 AMR AF: 0.0493

Gnomad4 ASJ AF: 0.0939

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.0685

Gnomad4 FIN AF: 0.0922

Gnomad4 NFE AF: 0.0641

Gnomad4 OTH AF: 0.0516

Alfa AF: 0.0584 Hom.: 159

Bravo AF: 0.0438

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.0724

EpiControl AF: 0.0702

ClinVar

Significance: Benign

Submissions summary: Benign:18 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ser526Ser in exon 15 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 7.0% (600/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs34012042). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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	-	- -

Tuberous sclerosis 2 Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 17, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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.1578C>T (p.Ser526Ser) 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. 4/5 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 6932/120900 control chromosomes (259 homozygotes) at a frequency of 0.0573366, which is approximately 834 times the estimated maximal expected allele frequency of a pathogenic TSC2 variant (0.0000688), indicating this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Tuberous sclerosis syndrome Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2024	- -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -

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)

-

- -

Lymphangiomyomatosis 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	-0.40
CADD	Benign	3.2
DANN	Benign	0.87

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: rs34012042; hg19: chr16-2114407; COSMIC: COSV54756543; COSMIC: COSV54756543;