rs1800742

Positions:

• chr16-2060804-G-A
• chr16-2060804-G-C

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.1110G>A​(p.Gln370=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,538 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (9 hom., cov: 33)
  • Exomes 𝑓: 0.011 (113 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20 O:1
• Conservation: PhyloP100: 2.02

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=-0.49).
• BP6: Variant 16-2060804-G-A is Benign according to our data. Variant chr16-2060804-G-A is described in ClinVar as [Benign]. Clinvar id is 49141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2060804-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00814 (1240/152292) while in subpopulation NFE AF= 0.0115 (782/68030). AF 95% confidence interval is 0.0108. There are 9 homozygotes in gnomad4. There are 581 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1240 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1110G>A	p.Gln370=	synonymous_variant	11/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1110G>A	p.Gln370=	synonymous_variant	11/42	5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes AF: 0.00817 AC: 1243 AN: 152174 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.0100 AC: 2511 AN: 250212 Hom.: 19 AF XY: 0.0101 AC XY: 1373 AN XY: 135582

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00512

Gnomad ASJ exome AF: 0.0335

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00549

Gnomad FIN exome AF: 0.00603

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0108 AC: 15849 AN: 1461246 Hom.: 113 Cov.: 32 AF XY: 0.0107 AC XY: 7781 AN XY: 726922

Gnomad4 AFR exome AF: 0.00266

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.0313

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00526

Gnomad4 FIN exome AF: 0.00649

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.00814 AC: 1240 AN: 152292 Hom.: 9 Cov.: 33 AF XY: 0.00780 AC XY: 581 AN XY: 74456

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.00863

Gnomad4 ASJ AF: 0.0346

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0116 Hom.: 11

Bravo AF: 0.00851

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0124

EpiControl AF: 0.0133

ClinVar

Significance: Benign

Submissions summary: Benign:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 16, 2021	- -
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	Gln370Gln in exon 11 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 1.5% (125/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs1800742). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 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, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 13, 2013	- -

Tuberous sclerosis 2 Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	May 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2019	- -

not provided Benign:4

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 23, 2016	Variant summary: The c.1110G>A (p.Gln370=) in TSC2 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.01 predominantly in individuals of European descent (0.016; 1083/65734) including 12 homozygous spread through 4 out of 6 populations. The variant of interest has been reported as polymorphism via publications and cited as Benign by multiple reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 13, 2023	- -

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 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. -
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

Nov 21, 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	-0.49
CADD	Benign	7.8
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1800742; hg19: chr16-2110805; COSMIC: COSV99554856; COSMIC: COSV99554856;