Genetic Variant TSC2:p.Thr1661Thr (chr16-2086865-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.4983C>T(p.Thr1661Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,589,816 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1661T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 124 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 101 hom. )

Consequence

TSC2
NM_000548.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:21O:1

Conservation

PhyloP100: 1.28

Publications

10 publications found

Variant links:

COSMIC-nc: COSV104375816

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 16-2086865-C-T is Benign according to our data. Variant chr16-2086865-C-T is described in ClinVar as Benign. ClinVar VariationId is 49467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.28 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0696 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
TSC2	NM_000548.5	MANE Select	c.4983C>T	p.Thr1661Thr	synonymous	Exon 38 of 42	NP_000539.2
TSC2	NM_001406663.1		c.4980C>T	p.Thr1660Thr	synonymous	Exon 38 of 42	NP_001393592.1
TSC2	NM_001114382.3		c.4914C>T	p.Thr1638Thr	synonymous	Exon 37 of 41	NP_001107854.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSC2	ENST00000219476.9	TSL:5 MANE Select	c.4983C>T	p.Thr1661Thr	synonymous	Exon 38 of 42	ENSP00000219476.3
TSC2	ENST00000350773.9	TSL:1	c.4914C>T	p.Thr1638Thr	synonymous	Exon 37 of 41	ENSP00000344383.4
TSC2	ENST00000401874.7	TSL:1	c.4782C>T	p.Thr1594Thr	synonymous	Exon 36 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes

AF:

0.0209

AC:

3178

AN:

152228

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0719

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00798

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000558

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.00543

AC:

1131

AN:

208278

AF XY:

0.00384

show subpopulations

Gnomad AFR exome

AF:

0.0743

Gnomad AMR exome

AF:

0.00521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000549

Gnomad NFE exome

AF:

0.000297

Gnomad OTH exome

AF:

0.00242

GnomAD4 exome

AF:

0.00225

AC:

3231

AN:

1437470

Hom.:

101

Cov.:

AF XY:

0.00190

AC XY:

1353

AN XY:

713260

show subpopulations

African (AFR)

AF:

0.0713

AC:

2344

AN:

32876

American (AMR)

AF:

0.00586

AC:

242

AN:

41330

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25712

East Asian (EAS)

AF:

0.00

AC:

AN:

38100

South Asian (SAS)

AF:

0.0000720

AC:

AN:

83336

European-Finnish (FIN)

AF:

0.0000397

AC:

AN:

50430

Middle Eastern (MID)

AF:

0.00318

AC:

AN:

5026

European-Non Finnish (NFE)

AF:

0.000266

AC:

293

AN:

1101170

Other (OTH)

AF:

0.00551

AC:

328

AN:

59490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

189

378

566

755

944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.0209

AC:

3177

AN:

152346

Hom.:

124

Cov.:

AF XY:

0.0198

AC XY:

1473

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0717

AC:

2981

AN:

41572

American (AMR)

AF:

0.00797

AC:

122

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000559

AC:

AN:

68038

Other (OTH)

AF:

0.0161

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

151

302

454

605

756

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0139

Hom.:

Bravo

AF:

0.0230

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Tuberous sclerosis 2 (5)

not provided (3)

Tuberous sclerosis syndrome (4)

Hereditary cancer-predisposing syndrome (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

7.6

(source)

DANN

Benign

0.69

PhyloP100

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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