chr16-2088095-C-T

Position:

chr16-2088095-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2

The NM_000548.5(TSC2):c.5116C>T(p.Arg1706Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,612,878 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1706H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:10O:1

Conservation

PhyloP100: 3.10

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 Likely_benign. Variant got -5 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 14 uncertain in NM_000548.5

BP4

Computational evidence support a benign effect (MetaRNN=0.16267908).

BP6

Variant 16-2088095-C-T is Benign according to our data. Variant chr16-2088095-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 49912.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=3, not_provided=1, Likely_benign=4}. Variant chr16-2088095-C-T is described in Lovd as [Likely_benign]. Variant chr16-2088095-C-T is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.5116C>T	p.Arg1706Cys	missense_variant	40/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.5116C>T	p.Arg1706Cys	missense_variant	40/42	5	NM_000548.5		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000296

AC:

AN:

250408

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.000371

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000381

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000409

AC:

598

AN:

1460576

Hom.:

Cov.:

AF XY:

0.000413

AC XY:

300

AN XY:

726624

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.000496

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000289

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000500

Hom.:

Bravo

AF:

0.000287

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 17, 2018	Variant summary: TSC2 c.5116C>T (p.Arg1706Cys) results in a non-conservative amino acid change located in the Rap GTPase activating protein domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), strongly suggesting that the variant is benign. The variant, c.5116C>T, has been reported in the literature in individuals affected with Tuberous Sclerosis Complex (Jozwiak_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Tuberous Sclerosis Complex. A functional study, Hoogeveen-Westerveld_2012, found the variant to act comparable to wild type protein and classified as probably neutral. An internal specimen reports the variant to co-occur with pathogenic FLCN, c.927_954dup28. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 29, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 20, 2021	- -

Tuberous sclerosis 2

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 09, 2023	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TSC2: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 11, 2019	This alteration is classified as likely 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

Benign:1Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Mar 17, 2022

ACMG categories: BP1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

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

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.023

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.16

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

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

1.8

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-4.6

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

REVEL

Pathogenic

0.68

Sift

Uncertain

0.027

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

Sift4G

Uncertain

0.0050

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

Polyphen

1.0

D;.;.;.;B;B;.;.;B;B;.;.;.;.;.

Vest4

0.46

MVP

0.89

ClinPred

0.059

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

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