rs1222477746

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000548.5(TSC2):c.278G>A(p.Arg93Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000278 in 1,439,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R93W) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 6.02

Publications

1 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1568372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.278G>A	p.Arg93Gln	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.278G>A	p.Arg93Gln	missense_variant	Exon 4 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000476

AC:

AN:

209906

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000325

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:

0.00000278

AC:

AN:

1439354

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713830

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33116

American (AMR)

AF:

0.00

AC:

AN:

41690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25656

East Asian (EAS)

AF:

0.00

AC:

AN:

38608

South Asian (SAS)

AF:

0.00

AC:

AN:

82502

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5392

European-Non Finnish (NFE)

AF:

0.00000272

AC:

AN:

1102152

Other (OTH)

AF:

0.00

AC:

AN:

59450

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Uncertain:2Benign:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2020

Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tuberous sclerosis syndrome

Uncertain:2

Oct 02, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with glutamine at codon 93 of the TSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 been identified in 1/209906 chromosomes 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. -

May 07, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with glutamine at codon 93 of the TSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC2-related disorders in the literature. This variant has been identified in 1/209906 chromosomes 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. -

Isolated focal cortical dysplasia type II

Uncertain:1

Oct 23, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Mar 14, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R93Q variant (also known as c.278G>A), located in coding exon 3 of the TSC2 gene, results from a G to A substitution at nucleotide position 278. The arginine at codon 93 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in an individual with a clinical diagnosis of tuberous sclerosis complex (TSC) (Togi S et al. Int J Mol Sci, 2022 Sep;23:). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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

0.076

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

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

Eigen

Benign

-0.14

Eigen_PC

Benign

0.0050

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

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

M_CAP

Benign

0.023

MetaRNN

Benign

0.16

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

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.0

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

PhyloP100

6.0

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.10

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

REVEL

Benign

0.21

Sift

Benign

0.42

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

Sift4G

Benign

0.38

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

Polyphen

1.0

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

Vest4

0.47

MutPred

0.35

Gain of disorder (P = 0.169);Gain of disorder (P = 0.169);Gain of disorder (P = 0.169);.;Gain of disorder (P = 0.169);Gain of disorder (P = 0.169);Gain of disorder (P = 0.169);Gain of disorder (P = 0.169);Gain of disorder (P = 0.169);.;Gain of disorder (P = 0.169);Gain of disorder (P = 0.169);Gain of disorder (P = 0.169);Gain of disorder (P = 0.169);.;

MVP

0.78

ClinPred

0.49

GERP RS

4.8

PromoterAI

-0.0075

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.045

gMVP

0.17

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs1222477746

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over