rs45517265

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2743-40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00885 in 1,611,124 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0091 ( 94 hom. )

Consequence

TSC2
NM_000548.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.789

Publications

3 publications found

Variant links:

COSMIC-nc: COSV104375713

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=-0.85).

BP6

Variant 16-2076451-A-G is Benign according to our data. Variant chr16-2076451-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 49756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00601 (913/151998) while in subpopulation NFE AF = 0.00969 (658/67934). AF 95% confidence interval is 0.00907. There are 3 homozygotes in GnomAd4. There are 390 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 913 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.2743-40A>G		intron_variant	Intron 24 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.2743-40A>G		intron_variant	Intron 24 of 41	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.00601

AC:

913

AN:

151880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00616

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00499

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00968

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00715

AC:

1787

AN:

249768

AF XY:

0.00761

show subpopulations

Gnomad AFR exome

AF:

0.00198

Gnomad AMR exome

AF:

0.00677

Gnomad ASJ exome

AF:

0.00420

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00126

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.00914

AC:

13338

AN:

1459126

Hom.:

Cov.:

AF XY:

0.00924

AC XY:

6708

AN XY:

725956

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

33458

American (AMR)

AF:

0.00696

AC:

311

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00444

AC:

116

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00731

AC:

630

AN:

86228

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

52034

Middle Eastern (MID)

AF:

0.0429

AC:

244

AN:

5690

European-Non Finnish (NFE)

AF:

0.0102

AC:

11347

AN:

1110882

Other (OTH)

AF:

0.00894

AC:

539

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

790

1579

2369

3158

3948

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00601

AC:

913

AN:

151998

Hom.:

Cov.:

AF XY:

0.00525

AC XY:

390

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

41454

American (AMR)

AF:

0.00615

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5130

South Asian (SAS)

AF:

0.00499

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00969

AC:

658

AN:

67934

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00755

Hom.:

Bravo

AF:

0.00680

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 21, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.85

CADD

Benign

1.1

(source)

DANN

Benign

0.32

PhyloP100

-0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(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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rs45517265

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