chr16-2084625-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP6

The NM_000548.5(TSC2):c.4403C>T(p.Pro1468Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000312 in 1,600,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1468A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.59

Publications

1 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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 16-2084625-C-T is Benign according to our data. Variant chr16-2084625-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 535938.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.4403C>T	p.Pro1468Leu	missense_variant	Exon 34 of 42	ENST00000219476.9	NP_000539.2	P49815-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.4403C>T	p.Pro1468Leu	missense_variant	Exon 34 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000840

AC:

AN:

238230

AF XY:

0.0000153

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1448686

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40644

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111766

Other (OTH)

AF:

0.00

AC:

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Oct 10, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P1468L variant (also known as c.4403C>T), located in coding exon 33 of the TSC2 gene, results from a C to T substitution at nucleotide position 4403. The proline at codon 1468 is replaced by leucine, an amino acid with similar properties. This nucleotide position is well conserved in available vertebrate species. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Tuberous sclerosis 2

Benign:1

Nov 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.;.;.;.;.;.;.;.;.;.;.;D;.;D

Eigen

Benign

-0.028

Eigen_PC

Benign

0.052

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Uncertain

0.62

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.2

M;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

4.6

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.5

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0010

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

Sift4G

Uncertain

0.0030

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

Polyphen

1.0

D;.;.;.;B;B;.;.;P;B;.;.;.;.;.

Vest4

0.72

MutPred

0.25

Loss of glycosylation at P1468 (P = 0.0543);.;.;.;.;.;.;Loss of glycosylation at P1468 (P = 0.0543);.;.;.;.;.;.;.;

MVP

0.91

ClinPred

0.90

GERP RS

4.0

Varity_R

0.39

gMVP

0.67

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over