16-2053367-C-T

Position:

chr16-2053367-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000548.5(TSC2):c.251C>T(p.Ala84Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 1,588,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. A84T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12O:2

Conservation

PhyloP100: 3.07

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:

TSC2 (HGNC:):

TSC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031080723).

BP6

Variant 16-2053367-C-T is Benign according to our data. Variant chr16-2053367-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 49212.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, not_provided=2, Benign=7}. Variant chr16-2053367-C-T is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.251C>T	p.Ala84Val	missense_variant	4/42	ENST00000219476.9	NP_000539.2	P49815-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.251C>T	p.Ala84Val	missense_variant	4/42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000322

AC:

AN:

208088

Hom.:

AF XY:

0.000410

AC XY:

AN XY:

112282

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000132

Gnomad ASJ exome

AF:

0.000654

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000693

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000394

Gnomad OTH exome

AF:

0.000569

GnomAD4 exome

AF:

0.000337

AC:

484

AN:

1436482

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

258

AN XY:

712226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000242

Gnomad4 ASJ exome

AF:

0.000898

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000816

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000315

Gnomad4 OTH exome

AF:

0.000438

GnomAD4 genome

AF:

0.000217

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000315

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000250

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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.251C>T (p.Ala84Val) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 20/32398 control chromosomes, predominantly observed in the European (Non-Finnish) and South Asian subpopulations at a frequency of 0.0008709 (14/16076) and 0.000704 (6/8528), respectively. This frequencies is about 10-13 times the estimated maximal expected allele frequency of a pathogenic TSC2 variant (0.0000688), suggesting this is likely a benign polymorphism found primarily in these two subpopulations. Co-occurrence of the variant of interest and a potential pathogenic TSC1 variant (c.1112T>G/p.Tyr297X) has been reported in one TSC patient. In addition, multiple clinical diagnostic laboratories classified this variant as likely benign. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TSC2: BP4 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2019	This variant is associated with the following publications: (PMID: 11208653, 28873162, 23514105) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 04, 2011	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 31, 2022	- -

Tuberous sclerosis syndrome

Uncertain:1Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 10, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 13, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 04, 2022	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. -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis

Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.41

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

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.065

MetaRNN

Benign

0.031

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

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.49

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

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.0

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

REVEL

Benign

0.23

Sift

Benign

0.43

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

Sift4G

Benign

0.68

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

Polyphen

0.016

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

Vest4

0.39

MVP

0.54

ClinPred

0.031

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.048

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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