Genetic Variant NM_000548.5:c.2580T>C (chr16-2075833-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.2580T>C(p.Phe860Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0786 in 1,612,884 control chromosomes in the GnomAD database, including 5,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 504 hom., cov: 33)

Exomes 𝑓: 0.079 ( 4803 hom. )

Consequence

TSC2
NM_000548.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.29

Publications

34 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=-0.85).

BP6

Variant 16-2075833-T-C is Benign according to our data. Variant chr16-2075833-T-C is described in ClinVar as Benign. ClinVar VariationId is 49573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.29 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.088 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.2580T>C	p.Phe860Phe	synonymous	Exon 23 of 42	NP_000539.2	P49815-1
TSC2	NM_001406663.1		c.2580T>C	p.Phe860Phe	synonymous	Exon 23 of 42	NP_001393592.1	A0A2R8Y6C9
TSC2	NM_001114382.3		c.2580T>C	p.Phe860Phe	synonymous	Exon 23 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.2580T>C	p.Phe860Phe	synonymous	Exon 23 of 42	ENSP00000219476.3	P49815-1
TSC2	ENST00000350773.9	TSL:1	c.2580T>C	p.Phe860Phe	synonymous	Exon 23 of 41	ENSP00000344383.4	P49815-4
TSC2	ENST00000401874.7	TSL:1	c.2580T>C	p.Phe860Phe	synonymous	Exon 23 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes

AF:

0.0781

AC:

11884

AN:

152088

Hom.:

502

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0904

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0553

Gnomad ASJ

AF:

0.0798

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.0607

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0790

Gnomad OTH

AF:

0.0655

GnomAD2 exomes

AF:

0.0697

AC:

17460

AN:

250520

AF XY:

0.0707

show subpopulations

Gnomad AFR exome

AF:

0.0888

Gnomad AMR exome

AF:

0.0353

Gnomad ASJ exome

AF:

0.0766

Gnomad EAS exome

AF:

0.00142

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.0819

Gnomad OTH exome

AF:

0.0694

GnomAD4 exome

AF:

0.0786

AC:

114807

AN:

1460678

Hom.:

4803

Cov.:

AF XY:

0.0778

AC XY:

56567

AN XY:

726662

show subpopulations

African (AFR)

AF:

0.0866

AC:

2899

AN:

33478

American (AMR)

AF:

0.0363

AC:

1623

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0794

AC:

2075

AN:

26128

East Asian (EAS)

AF:

0.000579

AC:

AN:

39698

South Asian (SAS)

AF:

0.0642

AC:

5538

AN:

86258

European-Finnish (FIN)

AF:

0.113

AC:

5889

AN:

52306

Middle Eastern (MID)

AF:

0.0685

AC:

395

AN:

5768

European-Non Finnish (NFE)

AF:

0.0827

AC:

91956

AN:

1111948

Other (OTH)

AF:

0.0730

AC:

4409

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

6866

13732

20599

27465

34331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3398

6796

10194

13592

16990

<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:

0.0781

AC:

11892

AN:

152206

Hom.:

504

Cov.:

AF XY:

0.0789

AC XY:

5871

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0904

AC:

3755

AN:

41538

American (AMR)

AF:

0.0553

AC:

846

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0798

AC:

277

AN:

3472

East Asian (EAS)

AF:

0.00174

AC:

AN:

5172

South Asian (SAS)

AF:

0.0603

AC:

291

AN:

4824

European-Finnish (FIN)

AF:

0.111

AC:

1173

AN:

10596

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0790

AC:

5374

AN:

67992

Other (OTH)

AF:

0.0648

AC:

137

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

571

1142

1713

2284

2855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<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:

0.0741

Hom.:

660

Bravo

AF:

0.0732

Asia WGS

AF:

0.0370

AC:

127

AN:

3478

EpiCase

AF:

0.0806

EpiControl

AF:

0.0741

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Tuberous sclerosis 2 (5)

not provided (4)

Tuberous sclerosis syndrome (4)

Hereditary cancer-predisposing syndrome (1)

Lymphangiomyomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.079

(source)

DANN

Benign

0.47

PhyloP100

-2.3

Mutation Taster

=99/1

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over