Genetic Variant TSC2:p.Asp1734Asp (chr16-2088268-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000548.5(TSC2):c.5202T>C(p.Asp1734Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,586,204 control chromosomes in the GnomAD database, including 38,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10451 hom., cov: 32)

Exomes 𝑓: 0.18 ( 28473 hom. )

Consequence

TSC2
NM_000548.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19O:2

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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 16-2088268-T-C is Benign according to our data. Variant chr16-2088268-T-C is described in ClinVar as Benign. ClinVar VariationId is 49895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.915 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

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	UniProt
TSC2	NM_000548.5	MANE Select	c.5202T>C	p.Asp1734Asp	synonymous	Exon 41 of 42	NP_000539.2	P49815-1
TSC2	NM_001406663.1		c.5199T>C	p.Asp1733Asp	synonymous	Exon 41 of 42	NP_001393592.1	A0A2R8Y6C9
TSC2	NM_001114382.3		c.5133T>C	p.Asp1711Asp	synonymous	Exon 40 of 41	NP_001107854.1	P49815-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSC2	ENST00000219476.9	TSL:5 MANE Select	c.5202T>C	p.Asp1734Asp	synonymous	Exon 41 of 42	ENSP00000219476.3	P49815-1
TSC2	ENST00000350773.9	TSL:1	c.5133T>C	p.Asp1711Asp	synonymous	Exon 40 of 41	ENSP00000344383.4	P49815-4
TSC2	ENST00000401874.7	TSL:1	c.5001T>C	p.Asp1667Asp	synonymous	Exon 39 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes

AF:

0.345

AC:

45504

AN:

131840

Hom.:

10415

Cov.:

show subpopulations

Gnomad AFR

AF:

0.674

Gnomad AMI

AF:

0.233

Gnomad AMR

AF:

0.229

Gnomad ASJ

AF:

0.227

Gnomad EAS

AF:

0.00166

Gnomad SAS

AF:

0.0944

Gnomad FIN

AF:

0.233

Gnomad MID

AF:

0.257

Gnomad NFE

AF:

0.209

Gnomad OTH

AF:

0.298

GnomAD2 exomes

AF:

0.178

AC:

44601

AN:

249878

AF XY:

0.169

show subpopulations

Gnomad AFR exome

AF:

0.658

Gnomad AMR exome

AF:

0.113

Gnomad ASJ exome

AF:

0.209

Gnomad EAS exome

AF:

0.000388

Gnomad FIN exome

AF:

0.207

Gnomad NFE exome

AF:

0.177

Gnomad OTH exome

AF:

0.176

GnomAD4 exome

AF:

0.179

AC:

259701

AN:

1454234

Hom.:

28473

Cov.:

AF XY:

0.174

AC XY:

126080

AN XY:

723304

show subpopulations

African (AFR)

AF:

0.661

AC:

22125

AN:

33462

American (AMR)

AF:

0.123

AC:

5440

AN:

44160

Ashkenazi Jewish (ASJ)

AF:

0.209

AC:

5445

AN:

26076

East Asian (EAS)

AF:

0.000349

AC:

AN:

37302

South Asian (SAS)

AF:

0.0830

AC:

7119

AN:

85724

European-Finnish (FIN)

AF:

0.206

AC:

10716

AN:

52104

Middle Eastern (MID)

AF:

0.189

AC:

1089

AN:

5754

European-Non Finnish (NFE)

AF:

0.177

AC:

195945

AN:

1109456

Other (OTH)

AF:

0.196

AC:

11809

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

14307

28615

42922

57230

71537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7014

14028

21042

28056

35070

<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:

0.346

AC:

45598

AN:

131970

Hom.:

10451

Cov.:

AF XY:

0.338

AC XY:

21867

AN XY:

64624

show subpopulations

African (AFR)

AF:

0.674

AC:

26810

AN:

39782

American (AMR)

AF:

0.229

AC:

3003

AN:

13096

Ashkenazi Jewish (ASJ)

AF:

0.227

AC:

671

AN:

2960

East Asian (EAS)

AF:

0.00166

AC:

AN:

3610

South Asian (SAS)

AF:

0.0941

AC:

375

AN:

3984

European-Finnish (FIN)

AF:

0.233

AC:

2179

AN:

9350

Middle Eastern (MID)

AF:

0.248

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.209

AC:

11814

AN:

56500

Other (OTH)

AF:

0.294

AC:

531

AN:

1806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1255

2510

3765

5020

6275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

394

788

1182

1576

1970

<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:

0.205

Hom.:

8412

Bravo

AF:

0.315

EpiCase

AF:

0.179

EpiControl

AF:

0.170

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (4)

Tuberous sclerosis 2 (4)

Tuberous sclerosis syndrome (4)

Hereditary cancer-predisposing syndrome (1)

Polycystic kidney disease, adult type (1)

Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

6.8

(source)

DANN

Benign

0.81

PhyloP100

0.92

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over