rs369932305

chr16-2053441-G-Achr16-2053441-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6

The NM_000548.5(TSC2):c.325G>A(p.Val109Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,575,008 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V109L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.43

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32235703).

BP6

Variant 16-2053441-G-A is Benign according to our data. Variant chr16-2053441-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207698.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}. Variant chr16-2053441-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.325G>A	p.Val109Met	missense_variant	4/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.325G>A	p.Val109Met	missense_variant	4/42	5	NM_000548.5		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000843

AC:

AN:

1422792

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

704108

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:

0.0000370

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000824

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000169

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 22, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Tuberous sclerosis syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 18, 2023

This missense variant replaces valine with methionine at codon 109 of the TSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The p.V109M variant (also known as c.325G>A), located in coding exon 3 of the TSC2 gene, results from a G to A substitution at nucleotide position 325. The valine at codon 109 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Benign

-0.11

Cadd

Benign

Dann

Benign

0.63

DEOGEN2

Uncertain

0.68

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

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.32

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

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

1.1

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

MutationTaster

Benign

1.0

D;N;N;N;N;N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.0

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

REVEL

Uncertain

0.59

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0060

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

Polyphen

0.99

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

Vest4

0.66

MVP

0.71

ClinPred

0.50

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.43

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