NM_000548.5:c.2639+44C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000548.5(TSC2):c.2639+44C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,612,368 control chromosomes in the GnomAD database, including 17,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 6778 hom., cov: 33)

Exomes 𝑓: 0.094 ( 10713 hom. )

Consequence

TSC2
NM_000548.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 0.683

Publications

10 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: 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=-0.91).

BP6

Variant 16-2075936-C-G is Benign according to our data. Variant chr16-2075936-C-G is described in ClinVar as Benign. ClinVar VariationId is 50084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.2639+44C>G		intron_variant	Intron 23 of 41	ENST00000219476.9	NP_000539.2	P49815-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.2639+44C>G		intron_variant	Intron 23 of 41	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.213

AC:

32423

AN:

152140

Hom.:

6741

Cov.:

show subpopulations

Gnomad AFR

AF:

0.547

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.129

Gnomad ASJ

AF:

0.102

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0624

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.0812

Gnomad OTH

AF:

0.183

GnomAD2 exomes

AF:

0.107

AC:

26715

AN:

249504

AF XY:

0.0983

show subpopulations

Gnomad AFR exome

AF:

0.554

Gnomad AMR exome

AF:

0.0695

Gnomad ASJ exome

AF:

0.101

Gnomad EAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.0846

Gnomad OTH exome

AF:

0.0950

GnomAD4 exome

AF:

0.0935

AC:

136523

AN:

1460110

Hom.:

10713

Cov.:

AF XY:

0.0907

AC XY:

65924

AN XY:

726460

show subpopulations

African (AFR)

AF:

0.565

AC:

18912

AN:

33462

American (AMR)

AF:

0.0746

AC:

3335

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

2716

AN:

26116

East Asian (EAS)

AF:

0.000202

AC:

AN:

39686

South Asian (SAS)

AF:

0.0641

AC:

5530

AN:

86236

European-Finnish (FIN)

AF:

0.112

AC:

5872

AN:

52312

Middle Eastern (MID)

AF:

0.118

AC:

679

AN:

5764

European-Non Finnish (NFE)

AF:

0.0834

AC:

92738

AN:

1111468

Other (OTH)

AF:

0.112

AC:

6733

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

6891

13782

20672

27563

34454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3632

7264

10896

14528

18160

<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:

0.214

AC:

32509

AN:

152258

Hom.:

6778

Cov.:

AF XY:

0.211

AC XY:

15686

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.547

AC:

22724

AN:

41512

American (AMR)

AF:

0.129

AC:

1973

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.102

AC:

355

AN:

3472

East Asian (EAS)

AF:

0.000771

AC:

AN:

5186

South Asian (SAS)

AF:

0.0619

AC:

299

AN:

4832

European-Finnish (FIN)

AF:

0.110

AC:

1171

AN:

10606

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0812

AC:

5523

AN:

68032

Other (OTH)

AF:

0.181

AC:

382

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

993

1986

2979

3972

4965

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

280

560

840

1120

1400

<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:

0.0621

Hom.:

108

Bravo

AF:

0.228

Asia WGS

AF:

0.0740

AC:

257

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tuberous sclerosis 2

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.91

CADD

Benign

0.83

(source)

DANN

Benign

0.43

PhyloP100

0.68

Mutation Taster

=97/3

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

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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