16-2053342-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000548.5(TSC2):c.226C>T(p.His76Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,578,928 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H76H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000090 ( 2 hom. )

Consequence

TSC2
NM_000548.5 missense, splice_region

Scores

Splicing: ADA: 0.9585

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 2.90

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041187406).

BP6

Variant 16-2053342-C-T is Benign according to our data. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787. Variant chr16-2053342-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207787.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000591 (9/152362) while in subpopulation SAS AF = 0.00186 (9/4834). AF 95% confidence interval is 0.000971. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.226C>T	p.His76Tyr	missense_variant, splice_region_variant	Exon 4 of 42	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.226C>T	p.His76Tyr	missense_variant, splice_region_variant	Exon 4 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152244

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:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000153

AC:

AN:

195940

AF XY:

0.000162

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:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000904

AC:

129

AN:

1426566

Hom.:

Cov.:

AF XY:

0.000126

AC XY:

AN XY:

706424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32776

American (AMR)

AF:

0.0000253

AC:

AN:

39566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25478

East Asian (EAS)

AF:

0.00

AC:

AN:

37944

South Asian (SAS)

AF:

0.00144

AC:

117

AN:

81136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4796

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1095460

Other (OTH)

AF:

0.000153

AC:

AN:

58990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000591

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41590

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00186

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000109

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.000175

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Uncertain:2Benign:3

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 13, 2024

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. -

Dec 15, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 29, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28250423) -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TSC2: PP3, BS1 -

not specified

Benign:1

Feb 10, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. -

Tuberous sclerosis syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hereditary cancer-predisposing syndrome

Benign:1

Jun 03, 2022

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

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

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.041

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.22

MutationAssessor

Uncertain

2.1

M;.;.;.;M;M;.;.;M;.;M;.;.;.

PhyloP100

2.9

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.1

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

REVEL

Uncertain

0.57

Sift

Benign

0.031

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

Sift4G

Uncertain

0.012

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

Polyphen

0.99

D;.;.;.;.;D;.;.;P;.;.;.;.;.

Vest4

0.53

MutPred

0.40

Gain of methylation at K71 (P = 0.0573);Gain of methylation at K71 (P = 0.0573);Gain of methylation at K71 (P = 0.0573);.;Gain of methylation at K71 (P = 0.0573);Gain of methylation at K71 (P = 0.0573);Gain of methylation at K71 (P = 0.0573);Gain of methylation at K71 (P = 0.0573);Gain of methylation at K71 (P = 0.0573);Gain of methylation at K71 (P = 0.0573);Gain of methylation at K71 (P = 0.0573);Gain of methylation at K71 (P = 0.0573);Gain of methylation at K71 (P = 0.0573);.;

MVP

0.71

ClinPred

0.23

GERP RS

4.8

PromoterAI

0.027

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.45

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Benign

0.71

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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