Genetic Variant TSC2:c.336+32C>T (chr16-2053484-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001406693.1(TSC2):c.-1370C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00621 in 1,538,092 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0045 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0064 ( 35 hom. )

Consequence

TSC2
NM_001406693.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1O:2

Conservation

PhyloP100: -1.69

Publications

3 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 16-2053484-C-T is Benign according to our data. Variant chr16-2053484-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 49809.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00451 (687/152260) while in subpopulation NFE AF = 0.00716 (487/68010). AF 95% confidence interval is 0.00663. There are 3 homozygotes in GnomAd4. There are 329 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 687 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406693.1. 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.336+32C>T		intron	N/A	NP_000539.2	P49815-1
TSC2	NM_001406693.1		c.-1370C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 41	NP_001393622.1
TSC2	NM_001406667.1		c.368C>T	p.Thr123Met	missense	Exon 4 of 40	NP_001393596.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TSC2	ENST00000219476.9	TSL:5 MANE Select	c.336+32C>T	intron	N/A	ENSP00000219476.3	P49815-1
TSC2	ENST00000350773.9	TSL:1	c.336+32C>T	intron	N/A	ENSP00000344383.4	P49815-4
TSC2	ENST00000401874.7	TSL:1	c.336+32C>T	intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes

AF:

0.00452

AC:

688

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00838

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00716

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.00491

AC:

722

AN:

147034

AF XY:

0.00519

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.000933

Gnomad ASJ exome

AF:

0.00584

Gnomad EAS exome

AF:

0.0000907

Gnomad FIN exome

AF:

0.00805

Gnomad NFE exome

AF:

0.00724

Gnomad OTH exome

AF:

0.00607

GnomAD4 exome

AF:

0.00640

AC:

8868

AN:

1385832

Hom.:

Cov.:

AF XY:

0.00643

AC XY:

4396

AN XY:

683716

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

31454

American (AMR)

AF:

0.00129

AC:

AN:

35748

Ashkenazi Jewish (ASJ)

AF:

0.00529

AC:

132

AN:

24972

East Asian (EAS)

AF:

0.00

AC:

AN:

35774

South Asian (SAS)

AF:

0.00454

AC:

358

AN:

78878

European-Finnish (FIN)

AF:

0.00972

AC:

441

AN:

45378

Middle Eastern (MID)

AF:

0.00213

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00707

AC:

7565

AN:

1070364

Other (OTH)

AF:

0.00489

AC:

282

AN:

57624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

461

921

1382

1842

2303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.00451

AC:

687

AN:

152260

Hom.:

Cov.:

AF XY:

0.00442

AC XY:

329

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

41562

American (AMR)

AF:

0.00196

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00311

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00838

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00716

AC:

487

AN:

68010

Other (OTH)

AF:

0.00285

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

107

143

179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00444

Hom.:

Bravo

AF:

0.00403

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.22

(source)

DANN

Benign

0.33

PhyloP100

-1.7

PromoterAI

-0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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