chr16-2061778-T-C

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.1120-93T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 1,600,276 control chromosomes in the GnomAD database, including 288,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 25175 hom., cov: 32)

Exomes 𝑓: 0.60 ( 263536 hom. )

Consequence

TSC2
NM_000548.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -3.24

Publications

11 publications found

Variant links:

COSMIC-nc: COSV54772015

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=-0.89).

BP6

Variant 16-2061778-T-C is Benign according to our data. Variant chr16-2061778-T-C is described in ClinVar as [Benign]. Clinvar id is 49143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.1120-93T>C		intron_variant	Intron 11 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.1120-93T>C		intron_variant	Intron 11 of 41	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.570

AC:

86516

AN:

151802

Hom.:

25141

Cov.:

show subpopulations

Gnomad AFR

AF:

0.452

Gnomad AMI

AF:

0.698

Gnomad AMR

AF:

0.607

Gnomad ASJ

AF:

0.613

Gnomad EAS

AF:

0.806

Gnomad SAS

AF:

0.662

Gnomad FIN

AF:

0.575

Gnomad MID

AF:

0.620

Gnomad NFE

AF:

0.603

Gnomad OTH

AF:

0.578

GnomAD4 exome

AF:

0.601

AC:

870903

AN:

1448356

Hom.:

263536

Cov.:

AF XY:

0.604

AC XY:

435283

AN XY:

720816

show subpopulations

African (AFR)

AF:

0.451

AC:

14999

AN:

33260

American (AMR)

AF:

0.665

AC:

29407

AN:

44198

Ashkenazi Jewish (ASJ)

AF:

0.609

AC:

15842

AN:

26006

East Asian (EAS)

AF:

0.780

AC:

30860

AN:

39554

South Asian (SAS)

AF:

0.657

AC:

56158

AN:

85484

European-Finnish (FIN)

AF:

0.581

AC:

29775

AN:

51204

Middle Eastern (MID)

AF:

0.614

AC:

3422

AN:

5572

European-Non Finnish (NFE)

AF:

0.593

AC:

654032

AN:

1103152

Other (OTH)

AF:

0.608

AC:

36408

AN:

59926

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

19317

38634

57951

77268

96585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17864

35728

53592

71456

89320

<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:

0.570

AC:

86589

AN:

151920

Hom.:

25175

Cov.:

AF XY:

0.572

AC XY:

42463

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.452

AC:

18728

AN:

41406

American (AMR)

AF:

0.607

AC:

9274

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.613

AC:

2126

AN:

3468

East Asian (EAS)

AF:

0.806

AC:

4142

AN:

5140

South Asian (SAS)

AF:

0.663

AC:

3199

AN:

4824

European-Finnish (FIN)

AF:

0.575

AC:

6086

AN:

10584

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.603

AC:

40981

AN:

67906

Other (OTH)

AF:

0.583

AC:

1226

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1944

3889

5833

7778

9722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

748

1496

2244

2992

3740

<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:

0.591

Hom.:

90551

Bravo

AF:

0.566

Asia WGS

AF:

0.746

AC:

2588

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Tuberous sclerosis database (TSC2)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

Jun 18, 2018

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 60% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 56. Only high quality variants are reported. -

Tuberous sclerosis 2

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.050

(source)

DANN

Benign

0.34

PhyloP100

-3.2

Mutation Taster

=19/81

disease causing

(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