16-2076141-C-T

Position:

chr16-2076141-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000548.5(TSC2):c.2713C>T(p.Arg905Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R905G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 3.00

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-2076141-C-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 16-2076141-C-T is Pathogenic according to our data. Variant chr16-2076141-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2076141-C-T is described in Lovd as [Pathogenic]. Variant chr16-2076141-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.2713C>T	p.Arg905Trp	missense_variant	24/42	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.2713C>T	p.Arg905Trp	missense_variant	24/42	5	NM_000548.5	ENSP00000219476		P49815-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461568

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 905 of the TSC2 protein (p.Arg905Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (PMID: 9463313, 12015165, 17120248, 19259131, 22867869). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12404). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. Experimental studies have shown that this missense change affects TSC2 function (PMID: 21309039). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg905 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9829910, 17120248, 22867869, 25432535). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 22, 2023	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17120248, 29458892, 32917966, 14641237, 29196670]. Functional studies indicate this variant impacts protein function [PMID: 17120248, 21309039]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 23, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2021	Published functional studies demonstrate a damaging effect on the TSC1-TSC2 complex (Hoogeveen-Westerveld et al. 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31447099, 25782670, 12015165, 19259131, 17304050, 14641237, 9463313, 22867869, 17120248, 22805177, 10205261, 23081885, 29196670, 31855466, 21309039) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 19, 2024	PP3, PP4, PM2, PM5, PM6, PS3, PS4_moderate -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Tuberous sclerosis syndrome

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2018	The p.Arg905Trp variant in TSC2 has been previously reported in more than 25 ind ividuals with tuberous sclerosis complex, including at least one de novo occurre nce (TSC; Au 1998, Sancak 2005, Jansen 2006, Le Caignec 2009, Hoogeveen-Westerve ld 2011, van Eeghen 2013, Tuberous Sclerosis Project: http://tsc-project.partner s.org/index.htm, Tuberous sclerosis LOVD database: http://chromium.lovd.nl/LOVD2 /TSC) and has also been reported by other clinical laboratories in ClinVar (Vari ation ID: 12404). In vitro functional studies provide some evidence that the p. Arg905Trp variant may impact protein function (Jansen 2006, Hoogeveen-Westerveld 2011). This variant was absent from large population studies. Computational pr ediction tools and conservation analysis suggest that the p.Arg905Trp variant ma y impact the protein. Another variant at the same amino acid position (p.Arg905G ln) has been reported in individuals with TSC (Beauchamp 1998, Yamamoto 2002, Ja nsen 2006, van Eeghen 2013, Tyburczy 2015, Tuberous Sclerosis Project: http://ts c-project.partners.org/index.htm), suggesting that changes at this amino acid po sition are not tolerated. In summary, this variant meets criteria to be classif ied as pathogenic for TSC in an autosomal dominant manner based upon presence in multiple affected individuals, including a de novo occurrence, absence from the general population and functional and computational evidence. ACMG/AMP Criteria applied: PS4, PM6, PM2, PP3, PS3_Supporting. -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 30, 2021

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2022

The p.R905W pathogenic mutation (also known as c.2713C>T), located in coding exon 23 of the TSC2 gene, results from a C to T substitution at nucleotide position 2713. The arginine at codon 905 is replaced by tryptophan, an amino acid with dissimilar properties. The p.R905W pathogenic variant has been reported as a recurrent de novo alteration in patients diagnosed with TSC (Au KS et al. Am. J. Hum. Genet., 1998 Feb;62:286-94; Jansen AC et al. Ann. Neurol. 2006 Nov;60(5):528-39; Le Caignec C et al. Eur. J. Hum. Genet., 2009 Sep;17:1165-70; http://www.lovd.nl/TSC2). Two additional mutations at codon 905 (p.R905Q and p.R905G) have been reported in numerous TSC families to date. Functional studies indicate that p.R905W disrupts tuberin activity and is pathogenic (Jansen AC et al. Ann. Neurol. 2006 Nov;60(5):528-39; Hoogeveen-Westerveld M et al. Hum. Mutat., 2011 Apr;32:424-35). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.;.;.;.;.;.;.;.;.;.;.;D;.;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.7

M;.;.;.;M;M;.;.;.;M;.;M;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-7.2

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

Sift4G

Pathogenic

0.0010

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

Polyphen

1.0

D;.;.;.;D;D;.;.;D;D;.;.;.;.;.

Vest4

0.98

MutPred

0.88

Gain of ubiquitination at K906 (P = 0.0497);Gain of ubiquitination at K906 (P = 0.0497);Gain of ubiquitination at K906 (P = 0.0497);.;Gain of ubiquitination at K906 (P = 0.0497);Gain of ubiquitination at K906 (P = 0.0497);Gain of ubiquitination at K906 (P = 0.0497);Gain of ubiquitination at K906 (P = 0.0497);.;Gain of ubiquitination at K906 (P = 0.0497);Gain of ubiquitination at K906 (P = 0.0497);Gain of ubiquitination at K906 (P = 0.0497);Gain of ubiquitination at K906 (P = 0.0497);Gain of ubiquitination at K906 (P = 0.0497);.;

MVP

1.0

ClinPred

0.99

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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