NM_000548.5:c.5204T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1BP4_ModerateBP6BS1BS2

The NM_000548.5(TSC2):c.5204T>C(p.Ile1735Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000049 in 1,612,946 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. I1735V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00032 ( 1 hom., cov: 34)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 3.92

Publications

2 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: Benign. The variant received -9 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 39 uncertain in NM_000548.5

BP4

Computational evidence support a benign effect (MetaRNN=0.08266613).

BP6

Variant 16-2088270-T-C is Benign according to our data. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952. Variant chr16-2088270-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 661952.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000322 (49/152186) while in subpopulation AMR AF = 0.00321 (49/15286). AF 95% confidence interval is 0.00249. There are 1 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.5204T>C	p.Ile1735Thr	missense_variant	Exon 41 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.5204T>C	p.Ile1735Thr	missense_variant	Exon 41 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000918

AC:

AN:

250616

AF XY:

0.0000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000578

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:

0.000327

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1460760

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726650

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000492

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111998

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000322

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00321

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000230

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Uncertain:2Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 27, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TSC2-related disorder

Benign:1

Aug 13, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome

Benign:1

Sep 28, 2021

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.0062

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Uncertain

0.55

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

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.88

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

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.083

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

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

1.7

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

PhyloP100

3.9

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.57

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

REVEL

Uncertain

0.58

Sift

Benign

1.0

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

Sift4G

Benign

0.33

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

Polyphen

0.0040

B;.;.;.;B;B;.;.;B;B;.;.;.;.;.

Vest4

0.34

MutPred

0.43

Loss of catalytic residue at P1737 (P = 0.0298);.;.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.95

ClinPred

0.049

GERP RS

3.1

Varity_R

0.088

gMVP

0.27

Mutation Taster

=87/13

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over