dbSNP rs137854239: TSC2:p.Phe1510del (chr16-2084980-CCTT-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1PM4_SupportingBP6BS1BS2

The NM_000548.5(TSC2):c.4527_4529delCTT(p.Phe1510del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00521 in 1,613,366 control chromosomes in the GnomAD database, including 44 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F1509F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0036 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0054 ( 41 hom. )

Consequence

TSC2
NM_000548.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:26O:3

Conservation

PhyloP100: 6.16

Publications

9 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: Likely_benign. The variant received -6 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 37 uncertain in NM_000548.5

PM4

Nonframeshift variant in NON repetitive region in NM_000548.5. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 16-2084980-CCTT-C is Benign according to our data. Variant chr16-2084980-CCTT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 49302.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00362 (552/152350) while in subpopulation SAS AF = 0.00911 (44/4828). AF 95% confidence interval is 0.00698. There are 3 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 552 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.4527_4529delCTT	p.Phe1510del	disruptive_inframe_deletion	Exon 35 of 42	NP_000539.2	P49815-1
TSC2	NM_001406663.1		c.4524_4526delCTT	p.Phe1509del	disruptive_inframe_deletion	Exon 35 of 42	NP_001393592.1	A0A2R8Y6C9
TSC2	NM_001114382.3		c.4458_4460delCTT	p.Phe1487del	disruptive_inframe_deletion	Exon 34 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.4527_4529delCTT	p.Phe1510del	disruptive_inframe_deletion	Exon 35 of 42	ENSP00000219476.3	P49815-1
TSC2	ENST00000350773.9	TSL:1	c.4458_4460delCTT	p.Phe1487del	disruptive_inframe_deletion	Exon 34 of 41	ENSP00000344383.4	P49815-4
TSC2	ENST00000401874.7	TSL:1	c.4326_4328delCTT	p.Phe1443del	disruptive_inframe_deletion	Exon 33 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes

AF:

0.00363

AC:

552

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.0302

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00911

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00394

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00539

AC:

1350

AN:

250376

AF XY:

0.00594

show subpopulations

Gnomad AFR exome

AF:

0.000681

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.0336

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00476

Gnomad NFE exome

AF:

0.00475

Gnomad OTH exome

AF:

0.00491

GnomAD4 exome

AF:

0.00538

AC:

7858

AN:

1461016

Hom.:

AF XY:

0.00562

AC XY:

4082

AN XY:

726798

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33480

American (AMR)

AF:

0.00152

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0338

AC:

883

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.00991

AC:

855

AN:

86258

European-Finnish (FIN)

AF:

0.00485

AC:

255

AN:

52622

Middle Eastern (MID)

AF:

0.00693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00475

AC:

5284

AN:

1111960

Other (OTH)

AF:

0.00745

AC:

450

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

540

1080

1620

2160

2700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

216

432

648

864

1080

<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:

0.00362

AC:

552

AN:

152350

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

281

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41588

American (AMR)

AF:

0.00209

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0302

AC:

105

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00911

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00612

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00394

AC:

268

AN:

68022

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

116

145

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:

0.00787

Hom.:

Bravo

AF:

0.00334

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00447

EpiControl

AF:

0.00528

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

Tuberous sclerosis 2 (7)

not provided (5)

Hereditary cancer-predisposing syndrome (3)

Tuberous sclerosis syndrome (4)

Lung lymphangioleiomyomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.2

Mutation Taster

=25/75

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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