16-2085072-C-T

Variant names:

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.4569+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,610,540 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 14 hom., cov: 34)

Exomes 𝑓: 0.014 ( 169 hom. )

Consequence

TSC2
NM_000548.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.450

Publications

4 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 16-2085072-C-T is Benign according to our data. Variant chr16-2085072-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49857.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 = 0.0105 (1595/152328) while in subpopulation NFE AF = 0.0187 (1270/68024). AF 95% confidence interval is 0.0178. There are 14 homozygotes in GnomAd4. There are 726 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 1595 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.4569+46C>T		intron_variant	Intron 35 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.4569+46C>T		intron_variant	Intron 35 of 41	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1595

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00602

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00527

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0187

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0103

AC:

2564

AN:

249256

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.00255

Gnomad AMR exome

AF:

0.00501

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00714

Gnomad NFE exome

AF:

0.0171

Gnomad OTH exome

AF:

0.0120

GnomAD4 exome

AF:

0.0139

AC:

20268

AN:

1458212

Hom.:

169

Cov.:

AF XY:

0.0137

AC XY:

9910

AN XY:

725618

show subpopulations

African (AFR)

AF:

0.00260

AC:

AN:

33404

American (AMR)

AF:

0.00503

AC:

225

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

284

AN:

26122

East Asian (EAS)

AF:

0.000101

AC:

AN:

39680

South Asian (SAS)

AF:

0.00355

AC:

306

AN:

86172

European-Finnish (FIN)

AF:

0.00760

AC:

397

AN:

52226

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0164

AC:

18213

AN:

1109872

Other (OTH)

AF:

0.0120

AC:

726

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1223

2446

3668

4891

6114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

642

1284

1926

2568

3210

<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:

0.0105

AC:

1595

AN:

152328

Hom.:

Cov.:

AF XY:

0.00975

AC XY:

726

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

41570

American (AMR)

AF:

0.00601

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00290

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00527

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0187

AC:

1270

AN:

68024

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

159

239

318

398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0151

Hom.:

Bravo

AF:

0.00958

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 15, 2018

GeneDx

Significance:Likely 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: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 2

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

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

-0.88

CADD

Benign

0.76

(source)

DANN

Benign

0.36

PhyloP100

0.45

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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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