Genetic Variant TSC2:p.Gly459Gly (chr16-2062987-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000548.5(TSC2):c.1377C>T(p.Gly459Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00073 in 1,550,996 control chromosomes in the GnomAD database, including 1 homozygotes. 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. G459G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00077 ( 1 hom. )

Consequence

TSC2
NM_000548.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: -1.98

Publications

6 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, G2P, Genomics England PanelApp
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

new If you want to explore the variant's impact on the transcript NM_000548.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 16-2062987-C-T is Benign according to our data. Variant chr16-2062987-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.98 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000407 (62/152358) while in subpopulation SAS AF = 0.00166 (8/4830). AF 95% confidence interval is 0.000824. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 62 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSC2	NM_000548.5	MANE Select	c.1377C>T	p.Gly459Gly	synonymous	Exon 14 of 42	NP_000539.2	P49815-1
TSC2	NM_001406663.1		c.1377C>T	p.Gly459Gly	synonymous	Exon 14 of 42	NP_001393592.1	A0A2R8Y6C9
TSC2	NM_001114382.3		c.1377C>T	p.Gly459Gly	synonymous	Exon 14 of 41	NP_001107854.1	P49815-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSC2	ENST00000219476.9	TSL:5 MANE Select	c.1377C>T	p.Gly459Gly	synonymous	Exon 14 of 42	ENSP00000219476.3	P49815-1
TSC2	ENST00000350773.9	TSL:1	c.1377C>T	p.Gly459Gly	synonymous	Exon 14 of 41	ENSP00000344383.4	P49815-4
TSC2	ENST00000401874.7	TSL:1	c.1377C>T	p.Gly459Gly	synonymous	Exon 14 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000661

AC:

103

AN:

155734

AF XY:

0.000634

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000750

Gnomad OTH exome

AF:

0.00136

GnomAD4 exome

AF:

0.000765

AC:

1070

AN:

1398638

Hom.:

Cov.:

AF XY:

0.000747

AC XY:

515

AN XY:

689866

show subpopulations

African (AFR)

AF:

0.000127

AC:

AN:

31584

American (AMR)

AF:

0.00168

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25170

East Asian (EAS)

AF:

0.00

AC:

AN:

35730

South Asian (SAS)

AF:

0.000189

AC:

AN:

79226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48904

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.000880

AC:

949

AN:

1078832

Other (OTH)

AF:

0.000725

AC:

AN:

57964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.000407

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41592

American (AMR)

AF:

0.000196

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00166

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000647

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000411

Hom.:

Bravo

AF:

0.000499

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Tuberous sclerosis 2 (5)

Hereditary cancer-predisposing syndrome (2)

not specified (2)

Tuberous sclerosis syndrome (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.62

(source)

DANN

Benign

0.75

PhyloP100

-2.0

PromoterAI

0.0072

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over