Genetic Variant TSC2:p.Ser526Ser (chr16-2064406-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000548.5(TSC2):c.1578C>T(p.Ser526Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0624 in 1,613,664 control chromosomes in the GnomAD database, including 3,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.049 ( 259 hom., cov: 33)

Exomes 𝑓: 0.064 ( 3284 hom. )

Consequence

TSC2
NM_000548.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19O:3

Conservation

PhyloP100: 0.0420

Publications

22 publications found

Variant links:

COSMIC-nc: COSV54756543

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 16-2064406-C-T is Benign according to our data. Variant chr16-2064406-C-T is described in ClinVar as Benign. ClinVar VariationId is 49162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.042 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0625 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.1578C>T	p.Ser526Ser	synonymous	Exon 15 of 42	NP_000539.2	P49815-1
TSC2	NM_001406663.1		c.1578C>T	p.Ser526Ser	synonymous	Exon 15 of 42	NP_001393592.1	A0A2R8Y6C9
TSC2	NM_001114382.3		c.1578C>T	p.Ser526Ser	synonymous	Exon 15 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.1578C>T	p.Ser526Ser	synonymous	Exon 15 of 42	ENSP00000219476.3	P49815-1
TSC2	ENST00000350773.9	TSL:1	c.1578C>T	p.Ser526Ser	synonymous	Exon 15 of 41	ENSP00000344383.4	P49815-4
TSC2	ENST00000401874.7	TSL:1	c.1578C>T	p.Ser526Ser	synonymous	Exon 15 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes

AF:

0.0489

AC:

7447

AN:

152232

Hom.:

258

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0493

Gnomad ASJ

AF:

0.0939

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0683

Gnomad FIN

AF:

0.0922

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0641

Gnomad OTH

AF:

0.0521

GnomAD2 exomes

AF:

0.0571

AC:

14349

AN:

251164

AF XY:

0.0597

show subpopulations

Gnomad AFR exome

AF:

0.0118

Gnomad AMR exome

AF:

0.0333

Gnomad ASJ exome

AF:

0.0992

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.0863

Gnomad NFE exome

AF:

0.0669

Gnomad OTH exome

AF:

0.0651

GnomAD4 exome

AF:

0.0638

AC:

93238

AN:

1461314

Hom.:

3284

Cov.:

AF XY:

0.0640

AC XY:

46536

AN XY:

726942

show subpopulations

African (AFR)

AF:

0.0104

AC:

348

AN:

33480

American (AMR)

AF:

0.0339

AC:

1515

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0997

AC:

2605

AN:

26136

East Asian (EAS)

AF:

0.000302

AC:

AN:

39700

South Asian (SAS)

AF:

0.0696

AC:

6003

AN:

86252

European-Finnish (FIN)

AF:

0.0834

AC:

4412

AN:

52914

Middle Eastern (MID)

AF:

0.102

AC:

585

AN:

5738

European-Non Finnish (NFE)

AF:

0.0667

AC:

74119

AN:

1111988

Other (OTH)

AF:

0.0603

AC:

3639

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

6288

12577

18865

25154

31442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2766

5532

8298

11064

13830

<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:

0.0489

AC:

7447

AN:

152350

Hom.:

259

Cov.:

AF XY:

0.0503

AC XY:

3746

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0132

AC:

549

AN:

41592

American (AMR)

AF:

0.0493

AC:

754

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0939

AC:

326

AN:

3472

East Asian (EAS)

AF:

0.000770

AC:

AN:

5192

South Asian (SAS)

AF:

0.0685

AC:

331

AN:

4830

European-Finnish (FIN)

AF:

0.0922

AC:

980

AN:

10624

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0641

AC:

4358

AN:

68018

Other (OTH)

AF:

0.0516

AC:

109

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

381

762

1144

1525

1906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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:

0.0564

Hom.:

215

Bravo

AF:

0.0438

Asia WGS

AF:

0.0360

AC:

126

AN:

3478

EpiCase

AF:

0.0724

EpiControl

AF:

0.0702

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Tuberous sclerosis 2 (5)

not provided (3)

Tuberous sclerosis syndrome (4)

Hereditary cancer-predisposing syndrome (1)

Lymphangiomyomatosis (1)

Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

3.2

(source)

DANN

Benign

0.87

PhyloP100

0.042

Mutation Taster

=99/1

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

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

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