16-2086865-C-T

Position:

• chr16-2086865-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.4983C>T​(p.Thr1661=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,589,816 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (124 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (101 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 1.28

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=-0.37).
• BP6: Variant 16-2086865-C-T is Benign according to our data. Variant chr16-2086865-C-T is described in ClinVar as [Benign]. Clinvar id is 49467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2086865-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4983C>T	p.Thr1661=	synonymous_variant	38/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4983C>T	p.Thr1661=	synonymous_variant	38/42	5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3178 AN: 152228 Hom.: 124 Cov.: 33

Gnomad AFR AF: 0.0719

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000558

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00543 AC: 1131 AN: 208278 Hom.: 39 AF XY: 0.00384 AC XY: 432 AN XY: 112486

Gnomad AFR exome AF: 0.0743

Gnomad AMR exome AF: 0.00521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000747

Gnomad FIN exome AF: 0.0000549

Gnomad NFE exome AF: 0.000297

Gnomad OTH exome AF: 0.00242

GnomAD4 exome AF: 0.00225 AC: 3231 AN: 1437470 Hom.: 101 Cov.: 31 AF XY: 0.00190 AC XY: 1353 AN XY: 713260

Gnomad4 AFR exome AF: 0.0713

Gnomad4 AMR exome AF: 0.00586

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000720

Gnomad4 FIN exome AF: 0.0000397

Gnomad4 NFE exome AF: 0.000266

Gnomad4 OTH exome AF: 0.00551

GnomAD4 genome AF: 0.0209 AC: 3177 AN: 152346 Hom.: 124 Cov.: 33 AF XY: 0.0198 AC XY: 1473 AN XY: 74492

Gnomad4 AFR AF: 0.0717

Gnomad4 AMR AF: 0.00797

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0120 Hom.: 33

Bravo AF: 0.0230

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 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	-	- -
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	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr1661Thr in exon 38 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 6.8% (297/4378) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs35534817). -

Tuberous sclerosis 2 Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 20, 2022	- -
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	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2017	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
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.4983C>T (p.Thr1661Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging 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 533/51540 control chromosomes (14 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0957862 (491/5126). This frequency is about 1393 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Tuberous sclerosis syndrome Benign:2 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
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	Feb 05, 2024	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.6
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs35534817; hg19: chr16-2136866; COSMIC: COSV104375816; COSMIC: COSV104375816;