rs137854220

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_000548.5(TSC2):c.5161-28_5161-25delTGAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,612,902 control chromosomes in the GnomAD database, including 128 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0082 ( 10 hom., cov: 33)

Exomes 𝑓: 0.010 ( 118 hom. )

Consequence

TSC2
NM_000548.5 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1O:2

Conservation

PhyloP100: 2.09

Publications

1 publications found

Variant links:

COSMIC-nc: COSV104573712

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 -10 ACMG points.

BP6

Variant 16-2088196-TAGTG-T is Benign according to our data. Variant chr16-2088196-TAGTG-T is described in ClinVar as Likely_benign. ClinVar VariationId is 49945.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00824 (1255/152226) while in subpopulation SAS AF = 0.0141 (68/4832). AF 95% confidence interval is 0.0115. There are 10 homozygotes in GnomAd4. There are 591 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1255 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	Effect	Exon Rank	Protein
TSC2	NM_000548.5	MANE Select	c.5161-28_5161-25delTGAG	intron	N/A	NP_000539.2
TSC2	NM_001406663.1		c.5158-28_5158-25delTGAG	intron	N/A	NP_001393592.1
TSC2	NM_001114382.3		c.5092-28_5092-25delTGAG	intron	N/A	NP_001107854.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TSC2	ENST00000219476.9	TSL:5 MANE Select	c.5161-28_5161-25delTGAG	intron	N/A	ENSP00000219476.3
TSC2	ENST00000350773.9	TSL:1	c.5092-28_5092-25delTGAG	intron	N/A	ENSP00000344383.4
TSC2	ENST00000401874.7	TSL:1	c.4960-28_4960-25delTGAG	intron	N/A	ENSP00000384468.2

Frequencies

GnomAD3 genomes

AF:

0.00827

AC:

1258

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.00577

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0122

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00860

AC:

2155

AN:

250500

AF XY:

0.00922

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.00393

Gnomad ASJ exome

AF:

0.00738

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00513

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.00850

GnomAD4 exome

AF:

0.0103

AC:

15017

AN:

1460676

Hom.:

118

AF XY:

0.0106

AC XY:

7718

AN XY:

726638

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

33478

American (AMR)

AF:

0.00385

AC:

172

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00639

AC:

167

AN:

26134

East Asian (EAS)

AF:

0.00144

AC:

AN:

39700

South Asian (SAS)

AF:

0.0165

AC:

1420

AN:

86250

European-Finnish (FIN)

AF:

0.00529

AC:

277

AN:

52328

Middle Eastern (MID)

AF:

0.00572

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0111

AC:

12307

AN:

1111920

Other (OTH)

AF:

0.00880

AC:

531

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

972

1944

2917

3889

4861

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

456

912

1368

1824

2280

<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:

0.00824

AC:

1255

AN:

152226

Hom.:

Cov.:

AF XY:

0.00794

AC XY:

591

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41536

American (AMR)

AF:

0.00778

AC:

119

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00577

AC:

AN:

3466

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.0141

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00358

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0122

AC:

830

AN:

67970

Other (OTH)

AF:

0.00992

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

136

203

271

339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0112

Hom.:

Bravo

AF:

0.00751

Asia WGS

AF:

0.00376

AC:

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1Other:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Tuberous sclerosis syndrome

Other:2

Apr 06, 2011

Tuberous sclerosis database (TSC2)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

Tuberous sclerosis database (TSC2)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

not provided

Benign:1

Jun 23, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over