chr16-2080189-C-T

Position:

chr16-2080189-C-T

Variant summary

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

The NM_000548.5(TSC2):c.3422C>T(p.Ala1141Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,612,968 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1141T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0055 ( 10 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 11 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19O:2

Conservation

PhyloP100: 2.77

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 chr16-2080188-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0060076714).

BP6

Variant 16-2080189-C-T is Benign according to our data. Variant chr16-2080189-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 49551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2080189-C-T is described in Lovd as [Benign]. Variant chr16-2080189-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00549 (836/152366) while in subpopulation AFR AF= 0.0193 (804/41590). AF 95% confidence interval is 0.0182. There are 10 homozygotes in gnomad4. There are 371 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 836 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.3422C>T	p.Ala1141Val	missense_variant	30/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.3422C>T	p.Ala1141Val	missense_variant	30/42	5	NM_000548.5		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.00548

AC:

835

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

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:

0.0000588

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00145

AC:

362

AN:

250372

Hom.:

AF XY:

0.000951

AC XY:

129

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.0195

Gnomad AMR exome

AF:

0.000954

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:

0.0000797

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000564

AC:

824

AN:

1460602

Hom.:

Cov.:

AF XY:

0.000482

AC XY:

350

AN XY:

726598

show subpopulations

Gnomad4 AFR exome

AF:

0.0203

Gnomad4 AMR exome

AF:

0.00125

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:

0.0000162

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00549

AC:

836

AN:

152366

Hom.:

Cov.:

AF XY:

0.00498

AC XY:

371

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0193

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00203

Hom.:

Bravo

AF:

0.00631

ESP6500AA

AF:

0.0189

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00180

AC:

219

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2013	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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 28, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 20, 2024	- -

Tuberous sclerosis 2

Benign:4

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	Mar 06, 2018	- -
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	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	TSC2: PM5, BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 25, 2016	- -

Tuberous sclerosis syndrome

Benign:2Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 11, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 19, 2015	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 06, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Uncertain

0.50

D;.;.;.;.;.;.;.;.;.;.;.;T;.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.88

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

MetaRNN

Benign

0.0060

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

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.81

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

MutationTaster

Benign

0.98

N;N;N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.3

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

REVEL

Uncertain

0.50

Sift

Benign

0.34

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

Sift4G

Benign

0.37

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

Polyphen

0.0010

B;.;.;.;B;B;.;.;B;B;.;.;.;.;.

Vest4

0.42

MVP

0.95

ClinPred

0.0037

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.017

gMVP

0.27

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

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