Genetic Variant TSC2:p.Pro1305Pro (chr16-2083726-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000548.5(TSC2):c.3915G>A(p.Pro1305Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,598,594 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1305P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.020 ( 130 hom., cov: 34)

Exomes 𝑓: 0.0021 ( 83 hom. )

Consequence

TSC2
NM_000548.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:21O:1

Conservation

PhyloP100: -2.39

Publications

8 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 16-2083726-G-A is Benign according to our data. Variant chr16-2083726-G-A is described in ClinVar as Benign. ClinVar VariationId is 49280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.39 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.069 is higher than 0.05.

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
TSC2	NM_000548.5	MANE Select	c.3915G>A	p.Pro1305Pro	synonymous	Exon 33 of 42	NP_000539.2
TSC2	NM_001406663.1		c.3912G>A	p.Pro1304Pro	synonymous	Exon 33 of 42	NP_001393592.1
TSC2	NM_001114382.3		c.3846G>A	p.Pro1282Pro	synonymous	Exon 32 of 41	NP_001107854.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSC2	ENST00000219476.9	TSL:5 MANE Select	c.3915G>A	p.Pro1305Pro	synonymous	Exon 33 of 42	ENSP00000219476.3
TSC2	ENST00000350773.9	TSL:1	c.3846G>A	p.Pro1282Pro	synonymous	Exon 32 of 41	ENSP00000344383.4
TSC2	ENST00000401874.7	TSL:1	c.3714G>A	p.Pro1238Pro	synonymous	Exon 31 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes

AF:

0.0204

AC:

3100

AN:

152168

Hom.:

129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0711

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00634

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.00493

AC:

1107

AN:

224328

AF XY:

0.00370

show subpopulations

Gnomad AFR exome

AF:

0.0681

Gnomad AMR exome

AF:

0.00374

Gnomad ASJ exome

AF:

0.000213

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000277

Gnomad OTH exome

AF:

0.00215

GnomAD4 exome

AF:

0.00206

AC:

2985

AN:

1446308

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

1242

AN XY:

717844

show subpopulations

African (AFR)

AF:

0.0702

AC:

2342

AN:

33384

American (AMR)

AF:

0.00410

AC:

172

AN:

41910

Ashkenazi Jewish (ASJ)

AF:

0.0000389

AC:

AN:

25708

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39184

South Asian (SAS)

AF:

0.000180

AC:

AN:

83474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51120

Middle Eastern (MID)

AF:

0.00261

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000155

AC:

171

AN:

1105864

Other (OTH)

AF:

0.00447

AC:

268

AN:

59920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

176

352

529

705

881

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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:

0.0204

AC:

3112

AN:

152286

Hom.:

130

Cov.:

AF XY:

0.0201

AC XY:

1499

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0711

AC:

2956

AN:

41550

American (AMR)

AF:

0.00634

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68016

Other (OTH)

AF:

0.0152

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

150

300

449

599

749

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00805

Hom.:

Bravo

AF:

0.0226

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Tuberous sclerosis 2 (5)

not provided (3)

Tuberous sclerosis syndrome (4)

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (2)

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.53

(source)

DANN

Benign

0.59

PhyloP100

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over