16-2088268-T-G

Variant names:

Variant summary

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

The NM_000548.5(TSC2):c.5202T>G(p.Asp1734Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000196 in 1,584,920 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1734N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.915

Publications

32 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.5202T>G	p.Asp1734Glu	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.5202T>G	p.Asp1734Glu	missense_variant	Exon 41 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.000221

AC:

AN:

131236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000230

Gnomad ASJ

AF:

0.000339

Gnomad EAS

AF:

0.000558

Gnomad SAS

AF:

0.000503

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000195

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

249878

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000138

AC:

AN:

1453556

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722996

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:

33442

American (AMR)

AF:

0.00

AC:

AN:

44086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.0000542

AC:

AN:

36906

South Asian (SAS)

AF:

0.00

AC:

AN:

85702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109296

Other (OTH)

AF:

0.00

AC:

AN:

60178

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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:

0.000221

AC:

AN:

131364

Hom.:

Cov.:

AF XY:

0.000233

AC XY:

AN XY:

64356

show subpopulations

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

African (AFR)

AF:

0.000253

AC:

AN:

39490

American (AMR)

AF:

0.000230

AC:

AN:

13052

Ashkenazi Jewish (ASJ)

AF:

0.000339

AC:

AN:

2952

East Asian (EAS)

AF:

0.000559

AC:

AN:

3578

South Asian (SAS)

AF:

0.000502

AC:

AN:

3982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

208

European-Non Finnish (NFE)

AF:

0.000195

AC:

AN:

56306

Other (OTH)

AF:

0.00

AC:

AN:

1792

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.237

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

8412

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability

Uncertain:1

Mar 20, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

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

Eigen

Benign

-0.0079

Eigen_PC

Benign

-0.062

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.81

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

M_CAP

Pathogenic

0.46

MetaRNN

Uncertain

0.70

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

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

0.74

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

PhyloP100

0.92

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.9

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

REVEL

Pathogenic

0.67

Sift

Uncertain

0.020

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

Sift4G

Benign

0.17

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

Polyphen

1.0

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

Vest4

0.43

MutPred

0.35

Loss of MoRF binding (P = 0.1222);.;.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.92

ClinPred

0.89

GERP RS

3.2

Varity_R

0.33

gMVP

0.48

Mutation Taster

=61/39

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over