rs35364892

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000548.5(TSC2):c.600-84C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00924 in 1,568,486 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0094 ( 104 hom. )

Consequence

TSC2
NM_000548.5 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: -0.508

Publications

2 publications found

Variant links:

COSMIC-nc: COSV54761845

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 16-2056112-C-T is Benign according to our data. Variant chr16-2056112-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 49409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0078 (1188/152232) while in subpopulation SAS AF = 0.0187 (90/4822). AF 95% confidence interval is 0.0156. There are 10 homozygotes in GnomAd4. There are 588 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1188 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.600-84C>T		intron_variant	Intron 6 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.600-84C>T		intron_variant	Intron 6 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes

AF:

0.00782

AC:

1189

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00760

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.0317

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0186

Gnomad FIN

AF:

0.00717

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00764

Gnomad OTH

AF:

0.00767

GnomAD2 exomes

AF:

0.00911

AC:

2183

AN:

239650

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.00666

Gnomad AMR exome

AF:

0.00286

Gnomad ASJ exome

AF:

0.0369

Gnomad EAS exome

AF:

0.000274

Gnomad FIN exome

AF:

0.00611

Gnomad NFE exome

AF:

0.00808

Gnomad OTH exome

AF:

0.00916

GnomAD4 exome

AF:

0.00939

AC:

13299

AN:

1416254

Hom.:

104

Cov.:

AF XY:

0.00982

AC XY:

6946

AN XY:

707014

show subpopulations

African (AFR)

AF:

0.00767

AC:

251

AN:

32708

American (AMR)

AF:

0.00342

AC:

152

AN:

44484

Ashkenazi Jewish (ASJ)

AF:

0.0371

AC:

959

AN:

25878

East Asian (EAS)

AF:

0.000152

AC:

AN:

39458

South Asian (SAS)

AF:

0.0195

AC:

1665

AN:

85232

European-Finnish (FIN)

AF:

0.00657

AC:

297

AN:

45218

Middle Eastern (MID)

AF:

0.00915

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00859

AC:

9269

AN:

1078544

Other (OTH)

AF:

0.0110

AC:

648

AN:

59052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

631

1261

1892

2522

3153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

376

752

1128

1504

1880

<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:

0.00780

AC:

1188

AN:

152232

Hom.:

Cov.:

AF XY:

0.00790

AC XY:

588

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00756

AC:

314

AN:

41548

American (AMR)

AF:

0.00373

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0317

AC:

110

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.0187

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00717

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00765

AC:

520

AN:

68014

Other (OTH)

AF:

0.00759

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

126

188

251

314

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:

0.0102

Hom.:

Bravo

AF:

0.00736

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 14, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Tuberous sclerosis syndrome

Other:1

Tuberous sclerosis database (TSC2)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.3

(source)

DANN

Benign

0.52

PhyloP100

-0.51

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over