Genetic Variant TSC2:p.Gln370Gln (chr16-2060804-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_StrongBP7BS1BS2

The NM_000548.5(TSC2):c.1110G>A(p.Gln370Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,538 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 9 hom., cov: 33)

Exomes 𝑓: 0.011 ( 113 hom. )

Consequence

TSC2
NM_000548.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:22O:1

Conservation

PhyloP100: 2.02

Publications

12 publications found

Variant links:

COSMIC-nc: COSV99554856

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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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=-0.49).

BP6

Variant 16-2060804-G-A is Benign according to our data. Variant chr16-2060804-G-A is described in ClinVar as Benign. ClinVar VariationId is 49141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.02 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00814 (1240/152292) while in subpopulation NFE AF = 0.0115 (782/68030). AF 95% confidence interval is 0.0108. There are 9 homozygotes in GnomAd4. There are 581 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1240 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.1110G>A	p.Gln370Gln	synonymous	Exon 11 of 42	NP_000539.2	P49815-1
TSC2	NM_001406663.1		c.1110G>A	p.Gln370Gln	synonymous	Exon 11 of 42	NP_001393592.1	A0A2R8Y6C9
TSC2	NM_001114382.3		c.1110G>A	p.Gln370Gln	synonymous	Exon 11 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.1110G>A	p.Gln370Gln	synonymous	Exon 11 of 42	ENSP00000219476.3	P49815-1
TSC2	ENST00000350773.9	TSL:1	c.1110G>A	p.Gln370Gln	synonymous	Exon 11 of 41	ENSP00000344383.4	P49815-4
TSC2	ENST00000401874.7	TSL:1	c.1110G>A	p.Gln370Gln	synonymous	Exon 11 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes

AF:

0.00817

AC:

1243

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00864

Gnomad ASJ

AF:

0.0346

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00683

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.0573

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.0100

AC:

2511

AN:

250212

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00512

Gnomad ASJ exome

AF:

0.0335

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00603

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.0162

GnomAD4 exome

AF:

0.0108

AC:

15849

AN:

1461246

Hom.:

113

Cov.:

AF XY:

0.0107

AC XY:

7781

AN XY:

726922

show subpopulations

African (AFR)

AF:

0.00266

AC:

AN:

33478

American (AMR)

AF:

0.00537

AC:

240

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0313

AC:

819

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00526

AC:

454

AN:

86240

European-Finnish (FIN)

AF:

0.00649

AC:

344

AN:

52982

Middle Eastern (MID)

AF:

0.0502

AC:

288

AN:

5740

European-Non Finnish (NFE)

AF:

0.0116

AC:

12844

AN:

1111894

Other (OTH)

AF:

0.0128

AC:

771

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

928

1856

2784

3712

4640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

478

956

1434

1912

2390

<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:

0.00814

AC:

1240

AN:

152292

Hom.:

Cov.:

AF XY:

0.00780

AC XY:

581

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00193

AC:

AN:

41554

American (AMR)

AF:

0.00863

AC:

132

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0346

AC:

120

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00663

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00433

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0548

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0115

AC:

782

AN:

68030

Other (OTH)

AF:

0.0142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

120

181

241

301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0108

Hom.:

Bravo

AF:

0.00851

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0124

EpiControl

AF:

0.0133

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Tuberous sclerosis 2 (5)

not provided (4)

Tuberous sclerosis syndrome (4)

Hereditary cancer-predisposing syndrome (1)

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.8

(source)

DANN

Benign

0.59

PhyloP100

2.0

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)

0.0

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