rs1800725

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_000548.5(TSC2):c.1100G>A(p.Arg367Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0161 in 1,613,742 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R367P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.012 ( 28 hom., cov: 32)

Exomes 𝑓: 0.017 ( 259 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:26O:2

Conservation

PhyloP100: 6.75

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-2060794-G-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.007699907).

BP6

Variant 16-2060794-G-A is Benign according to our data. Variant chr16-2060794-G-A is described in ClinVar as [Benign]. Clinvar id is 41725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2060794-G-A is described in Lovd as [Benign]. Variant chr16-2060794-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0123 (1874/152190) while in subpopulation NFE AF= 0.0178 (1213/67988). AF 95% confidence interval is 0.017. There are 28 homozygotes in gnomad4. There are 868 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1874 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.1100G>A	p.Arg367Gln	missense_variant	11/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.1100G>A	p.Arg367Gln	missense_variant	11/42	5	NM_000548.5	ENSP00000219476		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1874

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00287

Gnomad AMI

AF:

0.0187

Gnomad AMR

AF:

0.0138

Gnomad ASJ

AF:

0.0369

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0162

Gnomad FIN

AF:

0.00641

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0178

Gnomad OTH

AF:

0.0173

GnomAD3 exomes

AF:

0.0139

AC:

3487

AN:

250570

Hom.:

AF XY:

0.0145

AC XY:

1962

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.00358

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.0272

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0172

Gnomad FIN exome

AF:

0.00749

Gnomad NFE exome

AF:

0.0177

Gnomad OTH exome

AF:

0.0149

GnomAD4 exome

AF:

0.0165

AC:

24124

AN:

1461552

Hom.:

259

Cov.:

AF XY:

0.0166

AC XY:

12083

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.00326

Gnomad4 AMR exome

AF:

0.0110

Gnomad4 ASJ exome

AF:

0.0292

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0178

Gnomad4 FIN exome

AF:

0.00773

Gnomad4 NFE exome

AF:

0.0176

Gnomad4 OTH exome

AF:

0.0183

GnomAD4 genome

AF:

0.0123

AC:

1874

AN:

152190

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

868

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00286

Gnomad4 AMR

AF:

0.0138

Gnomad4 ASJ

AF:

0.0369

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0162

Gnomad4 FIN

AF:

0.00641

Gnomad4 NFE

AF:

0.0178

Gnomad4 OTH

AF:

0.0171

Alfa

AF:

0.0169

Hom.:

Bravo

AF:

0.0128

TwinsUK

AF:

0.0178

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00500

AC:

ESP6500EA

AF:

0.0201

AC:

173

ExAC

AF:

0.0136

AC:

1653

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0189

EpiControl

AF:

0.0185

ClinVar

Significance: Benign

Submissions summary: Benign:26Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 10, 2015	p.Arg367Gln in exon 11 of TSC2: This variant is not expected to have clinical si gnificance because it has been identified in 1.75% (1148/65946) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs1800725). -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:8

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 29196670, 24728327, 27153395, 28087349, 27884173, 19254590, 21309039, 11741833, 17304050, 22995991, 25281918, 15483652, 22703879) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TSC2: BP4, BS1, BS2 -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
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.1100G>A (p.Arg367Gln) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 1643/120374 control chromosomes (17 homozygotes) at a frequency of 0.0136491, which is approximately 199 times the estimated maximal expected allele frequency of a pathogenic TSC2 variant (0.0000688), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases and publications have classified this variant as benign, indicating rational as having a relatively high allele frequency in controls as well as being detected in unaffected family members of TSC patients. Taken together, this variant is classified as benign. -

Tuberous sclerosis 2

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 17, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 24, 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -

Tuberous sclerosis syndrome

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

T;.;.;.;.;.;.;.;.;.;.;.;T;.;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0077

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.3

L;.;.;.;L;L;.;.;.;L;.;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.2

N;.;.;N;.;N;.;.;N;N;.;.;.;.;N

REVEL

Benign

0.29

Sift

Benign

0.12

T;.;.;T;.;T;.;.;T;T;.;.;.;.;T

Sift4G

Benign

0.12

T;.;.;T;.;T;.;.;T;T;.;.;.;.;T

Polyphen

1.0

D;.;.;.;D;D;.;.;D;P;.;.;.;.;.

Vest4

0.59

ClinPred

0.019

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over