rs149543046

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000548.5(TSC2):c.1821G>A(p.Ala607Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,613,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A607A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

TSC2
NM_000548.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 0.334

Publications

3 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 16-2070560-G-A is Benign according to our data. Variant chr16-2070560-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 65382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.334 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000372 (544/1460802) while in subpopulation NFE AF = 0.000407 (453/1111998). AF 95% confidence interval is 0.000376. There are 0 homozygotes in GnomAdExome4. There are 262 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.1821G>A	p.Ala607Ala	synonymous_variant	Exon 17 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.1821G>A	p.Ala607Ala	synonymous_variant	Exon 17 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000296

AC:

AN:

250376

AF XY:

0.000258

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.000897

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000399

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000372

AC:

544

AN:

1460802

Hom.:

Cov.:

AF XY:

0.000361

AC XY:

262

AN XY:

726708

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000246

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00138

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000573

AC:

AN:

52360

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000407

AC:

453

AN:

1111998

Other (OTH)

AF:

0.000497

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000473

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41468

American (AMR)

AF:

0.000327

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68036

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000343

Hom.:

Bravo

AF:

0.000601

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 15, 2025

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.

Tuberous sclerosis syndrome

Benign:2Other:1

Tuberous sclerosis database (TSC2)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 20, 2014

GeneDx

Significance: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.

Hereditary cancer-predisposing syndrome

Benign:2

Sep 22, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

Jan 08, 2015

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2

Benign:1

Jan 28, 2025

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TSC2: BP4, BP7

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

9.1

(source)

DANN

Benign

0.73

PhyloP100

0.33

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