16-2053417-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000548.5(TSC2):c.301G>T(p.Val101Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V101M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.69

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

tuberous sclerosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
tuberous sclerosis 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
lymphangioleiomyomatosis
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
tuberous sclerosis complex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TSC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.301G>T	p.Val101Leu	missense_variant	Exon 4 of 42	ENST00000219476.9	NP_000539.2	P49815-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.301G>T	p.Val101Leu	missense_variant	Exon 4 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1433192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710302

African (AFR)

AF:

0.00

AC:

AN:

32912

American (AMR)

AF:

0.00

AC:

AN:

40636

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25560

East Asian (EAS)

AF:

0.00

AC:

AN:

38230

South Asian (SAS)

AF:

0.00

AC:

AN:

81922

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5494

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098772

Other (OTH)

AF:

0.00

AC:

AN:

59262

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis syndrome

Uncertain:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tuberous sclerosis 2

Uncertain:1

Mar 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 101 of the TSC2 protein (p.Val101Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 664080). 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) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

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

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.098

MetaRNN

Uncertain

0.59

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

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.8

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

PhyloP100

9.7

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.7

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

REVEL

Uncertain

0.39

Sift

Benign

0.030

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

Sift4G

Uncertain

0.028

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

Polyphen

0.97

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

Vest4

0.71

MutPred

0.49

Loss of ubiquitination at K106 (P = 0.1016);Loss of ubiquitination at K106 (P = 0.1016);Loss of ubiquitination at K106 (P = 0.1016);.;Loss of ubiquitination at K106 (P = 0.1016);Loss of ubiquitination at K106 (P = 0.1016);Loss of ubiquitination at K106 (P = 0.1016);Loss of ubiquitination at K106 (P = 0.1016);Loss of ubiquitination at K106 (P = 0.1016);.;Loss of ubiquitination at K106 (P = 0.1016);Loss of ubiquitination at K106 (P = 0.1016);Loss of ubiquitination at K106 (P = 0.1016);Loss of ubiquitination at K106 (P = 0.1016);.;

MVP

0.65

ClinPred

0.92

GERP RS

4.8

PromoterAI

0.064

Neutral

(source)

Varity_R

0.29

gMVP

0.79

Mutation Taster

=54/46

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over