rs145470784

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_000548.5(TSC2):c.223G>A(p.Glu75Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,613,418 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E75G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense, splice_region

Scores

Splicing: ADA: 0.6989

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: 9.21

Publications

13 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 -12 ACMG points.

BP6

Variant 16-2050484-G-A is Benign according to our data. Variant chr16-2050484-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 161399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.223G>A	p.Glu75Lys	missense_variant, splice_region_variant	Exon 3 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.223G>A	p.Glu75Lys	missense_variant, splice_region_variant	Exon 3 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000124

AC:

AN:

250806

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000148

AC:

217

AN:

1461304

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

116

AN XY:

726954

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.0000671

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000175

AC:

194

AN:

1111688

Other (OTH)

AF:

0.0000497

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000112

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41400

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.000156

Hom.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Benign:3

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 2025

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TSC2: BP1, BS2 -

Feb 11, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27153395, 19254590, 25637381, 29655203) -

Hereditary cancer-predisposing syndrome

Benign:2

Jun 05, 2025

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. -

May 28, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Tuberous sclerosis syndrome

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TSC2-related disorder

Benign:1

Mar 13, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D;D;T;D;T;D;D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.53

D;D;D;D;D;D;D;D;T;D;T;D;D;D;D;D

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.9

L;.;.;.;L;L;.;.;L;L;.;.;L;.;.;.

PhyloP100

9.2

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.4

N;.;.;N;.;N;.;.;N;N;.;.;.;.;.;N

REVEL

Uncertain

0.53

Sift

Benign

0.20

T;.;.;D;.;D;.;.;D;D;.;.;.;.;.;D

Sift4G

Uncertain

0.020

D;.;.;D;.;D;.;.;D;D;.;.;.;.;.;D

Polyphen

0.41

B;.;.;.;.;B;.;.;P;B;.;.;.;.;.;.

Vest4

0.78

MVP

0.90

ClinPred

0.20

GERP RS

4.8

Varity_R

0.32

gMVP

0.59

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.70

dbscSNV1_RF

Benign

0.65

Splicevardb

1.0

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