Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_000548.5(TSC2):c.1747G>A(p.Ala583Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00447 in 1,613,418 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A583V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 20 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23O:2

Conservation

PhyloP100: 8.07

Publications

29 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 -17 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 18 benign, 38 uncertain in NM_000548.5

PP3

Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.039117873).

BP6

Variant 16-2070486-G-A is Benign according to our data. Variant chr16-2070486-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00225 (343/152362) while in subpopulation NFE AF = 0.00416 (283/68032). AF 95% confidence interval is 0.00376. There are 1 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 343 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSC2	NM_000548.5	MANE Select	c.1747G>A	p.Ala583Thr	missense	Exon 17 of 42	NP_000539.2
TSC2	NM_001406663.1		c.1747G>A	p.Ala583Thr	missense	Exon 17 of 42	NP_001393592.1
TSC2	NM_001114382.3		c.1747G>A	p.Ala583Thr	missense	Exon 17 of 41	NP_001107854.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSC2	ENST00000219476.9	TSL:5 MANE Select	c.1747G>A	p.Ala583Thr	missense	Exon 17 of 42	ENSP00000219476.3
TSC2	ENST00000350773.9	TSL:1	c.1747G>A	p.Ala583Thr	missense	Exon 17 of 41	ENSP00000344383.4
TSC2	ENST00000401874.7	TSL:1	c.1747G>A	p.Ala583Thr	missense	Exon 17 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

343

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00416

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00202

AC:

507

AN:

250872

AF XY:

0.00214

show subpopulations

Gnomad AFR exome

AF:

0.000679

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00397

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00470

AC:

6866

AN:

1461056

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

3251

AN XY:

726832

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33480

American (AMR)

AF:

0.000492

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000532

AC:

AN:

52606

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00582

AC:

6470

AN:

1112002

Other (OTH)

AF:

0.00530

AC:

320

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

464

927

1391

1854

2318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.00225

AC:

343

AN:

152362

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

147

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41582

American (AMR)

AF:

0.000915

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00416

AC:

283

AN:

68032

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00300

Hom.:

Bravo

AF:

0.00216

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00165

AC:

200

EpiCase

AF:

0.00420

EpiControl

AF:

0.00421

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

not specified (8)

Tuberous sclerosis 2 (3)

Hereditary cancer-predisposing syndrome (2)

Tuberous sclerosis syndrome (3)

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.039

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

3.0

PhyloP100

8.1

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.77

MVP

0.90

ClinPred

0.057

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.61

Mutation Taster

=99/1

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

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

rs1800729

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over