rs140772300

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000548.5(TSC2):c.3287C>G(p.Ser1096Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,457,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. S1096P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.42

Publications

5 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3570742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.3287C>G	p.Ser1096Cys	missense_variant, splice_region_variant	Exon 29 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.3287C>G	p.Ser1096Cys	missense_variant, splice_region_variant	Exon 29 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000415

AC:

AN:

240976

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

6.86e-7

AC:

AN:

1457614

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724872

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.0000226

AC:

AN:

44300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26030

East Asian (EAS)

AF:

0.00

AC:

AN:

39554

South Asian (SAS)

AF:

0.00

AC:

AN:

85696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110774

Other (OTH)

AF:

0.00

AC:

AN:

60186

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Uncertain:1

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1096 of the TSC2 protein (p.Ser1096Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 957650). 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 disruptive. 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. -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2

Uncertain:1

Dec 22, 2023

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Jan 14, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S1096C variant (also known as c.3287C>G), located in coding exon 28 of the TSC2 gene, results from a C to G substitution at nucleotide position 3287. The serine at codon 1096 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.64

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

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

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

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.36

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

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.3

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

PhyloP100

5.4

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.1

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

REVEL

Uncertain

0.42

Sift

Benign

0.074

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

Sift4G

Benign

0.096

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

Polyphen

1.0

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

Vest4

0.47

MutPred

0.22

Loss of phosphorylation at S1096 (P = 0.0128);.;Loss of phosphorylation at S1096 (P = 0.0128);.;.;.;.;Loss of phosphorylation at S1096 (P = 0.0128);.;Loss of phosphorylation at S1096 (P = 0.0128);.;.;.;.;.;

MVP

0.88

ClinPred

0.41

GERP RS

4.7

Varity_R

0.15

gMVP

0.52

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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