rs757347786

Positions:

chr16-2072362-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2PP3_ModerateBS2

The NM_000548.5(TSC2):c.2219T>C(p.Met740Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense, splice_region

Scores

Splicing: ADA: 0.8769

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.95

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.927

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.2219T>C	p.Met740Thr	missense_variant, splice_region_variant	20/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.2219T>C	p.Met740Thr	missense_variant, splice_region_variant	20/42	5	NM_000548.5	ENSP00000219476		P49815-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250908

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2020	The p.M740T variant (also known as c.2219T>C), located in coding exon 19 of the TSC2 gene, results from a T to C substitution at nucleotide position 2219. The methionine at codon 740 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Tuberous sclerosis 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 24, 2023

This variant is present in population databases (rs757347786, gnomAD 0.02%). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 578982). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 740 of the TSC2 protein (p.Met740Thr). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

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

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.93

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

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.3

M;.;.;.;M;M;.;.;.;M;.;M;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.8

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

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

0.93

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

Vest4

0.85

MutPred

0.77

Loss of stability (P = 0.0098);Loss of stability (P = 0.0098);Loss of stability (P = 0.0098);.;Loss of stability (P = 0.0098);Loss of stability (P = 0.0098);Loss of stability (P = 0.0098);Loss of stability (P = 0.0098);.;Loss of stability (P = 0.0098);Loss of stability (P = 0.0098);Loss of stability (P = 0.0098);Loss of stability (P = 0.0098);Loss of stability (P = 0.0098);.;

MVP

0.92

ClinPred

0.70

GERP RS

5.2

Varity_R

0.82

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.88

dbscSNV1_RF

Pathogenic

0.78

SpliceAI score (max)

0.14

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