Genetic Variant TSC2:p.Arg691Arg (chr16-2071910-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.2073C>T(p.Arg691Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000453 in 1,592,702 control chromosomes in the GnomAD database, including 4 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. R691R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00045 ( 4 hom. )

Consequence

TSC2
NM_000548.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: -8.34

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: 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=-0.72).

BP6

Variant 16-2071910-C-T is Benign according to our data. Variant chr16-2071910-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-8.34 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000451 (650/1440330) while in subpopulation SAS AF = 0.00142 (118/83300). AF 95% confidence interval is 0.00121. There are 4 homozygotes in GnomAdExome4. There are 340 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 71 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.2073C>T	p.Arg691Arg	synonymous	Exon 19 of 42	NP_000539.2	P49815-1
TSC2	NM_001406663.1		c.2073C>T	p.Arg691Arg	synonymous	Exon 19 of 42	NP_001393592.1	A0A2R8Y6C9
TSC2	NM_001114382.3		c.2073C>T	p.Arg691Arg	synonymous	Exon 19 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.2073C>T	p.Arg691Arg	synonymous	Exon 19 of 42	ENSP00000219476.3	P49815-1
TSC2	ENST00000350773.9	TSL:1	c.2073C>T	p.Arg691Arg	synonymous	Exon 19 of 41	ENSP00000344383.4	P49815-4
TSC2	ENST00000401874.7	TSL:1	c.2073C>T	p.Arg691Arg	synonymous	Exon 19 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000933

AC:

195

AN:

208904

AF XY:

0.000998

show subpopulations

Gnomad AFR exome

AF:

0.000160

Gnomad AMR exome

AF:

0.0000639

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.000375

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000491

Gnomad OTH exome

AF:

0.00192

GnomAD4 exome

AF:

0.000451

AC:

650

AN:

1440330

Hom.:

Cov.:

AF XY:

0.000476

AC XY:

340

AN XY:

714542

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

33088

American (AMR)

AF:

0.0000944

AC:

AN:

42380

Ashkenazi Jewish (ASJ)

AF:

0.0105

AC:

268

AN:

25638

East Asian (EAS)

AF:

0.000181

AC:

AN:

38714

South Asian (SAS)

AF:

0.00142

AC:

118

AN:

83300

European-Finnish (FIN)

AF:

0.0000992

AC:

AN:

50388

Middle Eastern (MID)

AF:

0.00107

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.000160

AC:

176

AN:

1101790

Other (OTH)

AF:

0.00104

AC:

AN:

59418

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

122

162

203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000466

AC:

AN:

152372

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41594

American (AMR)

AF:

0.000261

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

3468

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.00112

Hom.:

Bravo

AF:

0.000567

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Tuberous sclerosis 2 (4)

Tuberous sclerosis syndrome (4)

Hereditary cancer-predisposing syndrome (2)

not provided (2)

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

-0.72

CADD

Benign

0.14

(source)

DANN

Benign

0.90

PhyloP100

-8.3

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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