16-2075833-T-C

Position:

• chr16-2075833-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.2580T>C​(p.Phe860Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0786 in 1,612,884 control chromosomes in the GnomAD database, including 5,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (504 hom., cov: 33)
  • Exomes 𝑓: 0.079 (4803 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18 O:2
• Conservation: PhyloP100: -2.29

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-2075833-T-C is Benign according to our data. Variant chr16-2075833-T-C is described in ClinVar as [Benign]. Clinvar id is 49573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2075833-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.088 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.2580T>C	p.Phe860Phe	synonymous_variant	23/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.2580T>C	p.Phe860Phe	synonymous_variant	23/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0781 AC: 11884 AN: 152088 Hom.: 502 Cov.: 33

Gnomad AFR AF: 0.0904

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0553

Gnomad ASJ AF: 0.0798

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0607

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0790

Gnomad OTH AF: 0.0655

GnomAD3 exomes AF: 0.0697 AC: 17460 AN: 250520 Hom.: 734 AF XY: 0.0707 AC XY: 9597 AN XY: 135806

Gnomad AFR exome AF: 0.0888

Gnomad AMR exome AF: 0.0353

Gnomad ASJ exome AF: 0.0766

Gnomad EAS exome AF: 0.00142

Gnomad SAS exome AF: 0.0634

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.0819

Gnomad OTH exome AF: 0.0694

GnomAD4 exome AF: 0.0786 AC: 114807 AN: 1460678 Hom.: 4803 Cov.: 33 AF XY: 0.0778 AC XY: 56567 AN XY: 726662

Gnomad4 AFR exome AF: 0.0866

Gnomad4 AMR exome AF: 0.0363

Gnomad4 ASJ exome AF: 0.0794

Gnomad4 EAS exome AF: 0.000579

Gnomad4 SAS exome AF: 0.0642

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.0827

Gnomad4 OTH exome AF: 0.0730

GnomAD4 genome AF: 0.0781 AC: 11892 AN: 152206 Hom.: 504 Cov.: 33 AF XY: 0.0789 AC XY: 5871 AN XY: 74420

Gnomad4 AFR AF: 0.0904

Gnomad4 AMR AF: 0.0553

Gnomad4 ASJ AF: 0.0798

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0603

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.0790

Gnomad4 OTH AF: 0.0648

Alfa AF: 0.0713 Hom.: 318

Bravo AF: 0.0732

Asia WGS AF: 0.0370 AC: 127 AN: 3478

EpiCase AF: 0.0806

EpiControl AF: 0.0741

ClinVar

Significance: Benign

Submissions summary: Benign:18 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Phe860Phe in exon 23 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 8.7% (381/4396) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs13337626). -
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	Eurofins Ntd Llc (ga)	Oct 16, 2014	- -

Tuberous sclerosis 2 Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -
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	Athena Diagnostics	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:4

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.2580T>C (p.Phe860Phe) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predicting no significant impact on splicing and alterations to ESE binding, however, these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 8679/119772 (1/13, 390 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic TSC2 variant of 1/14534, suggesting this variant is likely a benign polymorphism. In addition, multiple reputable clinical laboratories/databases cite the variant as "likely benign/benign." Therefore, the variant of interest has been 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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 19, 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. -

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	-0.85
CADD	Benign	0.079
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs13337626; hg19: chr16-2125834; COSMIC: COSV54756583; COSMIC: COSV54756583;