16-2086841-C-T

Position:

• chr16-2086841-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000548.5(TSC2):​c.4959C>T​(p.Ser1653Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,603,860 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1653S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0098 (16 hom., cov: 33)
  • Exomes 𝑓: 0.012 (142 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20 O:2
• Conservation: PhyloP100: -2.92

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=-0.81).
• BP6: Variant 16-2086841-C-T is Benign according to our data. Variant chr16-2086841-C-T is described in ClinVar as [Benign]. Clinvar id is 49818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2086841-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.92 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00983 (1497/152326) while in subpopulation NFE AF= 0.014 (954/68032). AF 95% confidence interval is 0.0133. There are 16 homozygotes in gnomad4. There are 748 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1497 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4959C>T	p.Ser1653Ser	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.4959C>T	p.Ser1653Ser	synonymous_variant	38/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00985 AC: 1499 AN: 152208 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00955 AC: 2217 AN: 232198 Hom.: 15 AF XY: 0.00962 AC XY: 1211 AN XY: 125836

Gnomad AFR exome AF: 0.00276

Gnomad AMR exome AF: 0.00666

Gnomad ASJ exome AF: 0.000415

Gnomad EAS exome AF: 0.000349

Gnomad SAS exome AF: 0.00125

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0122 AC: 17657 AN: 1451534 Hom.: 142 Cov.: 31 AF XY: 0.0117 AC XY: 8443 AN XY: 721418

Gnomad4 AFR exome AF: 0.00187

Gnomad4 AMR exome AF: 0.00799

Gnomad4 ASJ exome AF: 0.000500

Gnomad4 EAS exome AF: 0.000230

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.0181

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.00983 AC: 1497 AN: 152326 Hom.: 16 Cov.: 33 AF XY: 0.0100 AC XY: 748 AN XY: 74490

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0180

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00766 Hom.: 5

Bravo AF: 0.00954

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:20 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 07, 2022	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	Ser1653Ser 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 1.5% (127/8580) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs45517384). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University 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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 20, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2017	- -
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:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TSC2: BP4, BP7, BS1, BS2 -
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.4959C>T (p.Ser1653Ser) 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. 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 944/70720 control chromosomes (3 homozygotes) at a frequency of 0.0133484, which is approximately 194 times the estimated maximal expected allele frequency of a pathogenic TSC2 variant (0.0000688), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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 14, 2023	- -

Tuberous sclerosis syndrome Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
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. -

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. -

Tuberous sclerosis syndrome;C0751674: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	-0.81
CADD	Benign	0.14
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs45517384; hg19: chr16-2136842; COSMIC: COSV99238302; COSMIC: COSV99238302;