dbSNP rs45517204: TSC2:c.1839+6G>A (chr16-2070584-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000548.5(TSC2):c.1839+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00094 in 1,613,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00099 ( 0 hom. )

Consequence

TSC2
NM_000548.5 splice_region, intron

Scores

Splicing: ADA: 0.00002572

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:18O:1

Conservation

PhyloP100: 0.0760

Publications

4 publications found

Variant links:

COSMIC-nc: COSV104990149

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 -13 ACMG points.

BP4

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

BP6

Variant 16-2070584-G-A is Benign according to our data. Variant chr16-2070584-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 49658.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000453 (69/152350) while in subpopulation NFE AF = 0.000882 (60/68032). AF 95% confidence interval is 0.000703. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 69 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	Effect	Exon Rank	Protein	UniProt
TSC2	NM_000548.5	MANE Select	c.1839+6G>A	splice_region intron	N/A	NP_000539.2	P49815-1
TSC2	NM_001406663.1		c.1839+6G>A	splice_region intron	N/A	NP_001393592.1	A0A2R8Y6C9
TSC2	NM_001114382.3		c.1839+6G>A	splice_region intron	N/A	NP_001107854.1	P49815-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TSC2	ENST00000219476.9	TSL:5 MANE Select	c.1839+6G>A	splice_region intron	N/A	ENSP00000219476.3	P49815-1
TSC2	ENST00000350773.9	TSL:1	c.1839+6G>A	splice_region intron	N/A	ENSP00000344383.4	P49815-4
TSC2	ENST00000401874.7	TSL:1	c.1839+6G>A	splice_region intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000429

AC:

107

AN:

249704

AF XY:

0.000457

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000899

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000991

AC:

1448

AN:

1460652

Hom.:

Cov.:

AF XY:

0.000992

AC XY:

721

AN XY:

726624

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000383

AC:

AN:

52226

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00124

AC:

1376

AN:

1111986

Other (OTH)

AF:

0.000861

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

101

202

303

404

505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

116

174

232

290

<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:

0.000453

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41580

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.000640

Hom.:

Bravo

AF:

0.000487

EpiCase

AF:

0.000872

EpiControl

AF:

0.000889

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Tuberous sclerosis 2 (4)

Tuberous sclerosis syndrome (4)

Hereditary cancer-predisposing syndrome (2)

Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.0090

(source)

DANN

Benign

0.50

PhyloP100

0.076

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.0

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