rs878854085

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM2PP3_StrongBP6

The NM_000548.5(TSC2):c.2576A>C(p.Asn859Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. N859S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.03

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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

BP6

Variant 16-2075829-A-C is Benign according to our data. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997. Variant chr16-2075829-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 237997.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.2576A>C	p.Asn859Thr	missense_variant	Exon 23 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.2576A>C	p.Asn859Thr	missense_variant	Exon 23 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460712

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726674

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111960

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

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

Cov.:

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

Apr 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.N859T variant (also known as c.2576A>C), located in coding exon 22 of the TSC2 gene, results from an A to C substitution at nucleotide position 2576. The asparagine at codon 859 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Tuberous sclerosis 2

Benign:1

May 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

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

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.97

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

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

2.9

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

PhyloP100

9.0

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-4.2

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

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0080

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

Polyphen

1.0

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

Vest4

0.96

MutPred

0.86

Loss of stability (P = 0.04);Loss of stability (P = 0.04);Loss of stability (P = 0.04);.;Loss of stability (P = 0.04);Loss of stability (P = 0.04);Loss of stability (P = 0.04);Loss of stability (P = 0.04);.;Loss of stability (P = 0.04);Loss of stability (P = 0.04);Loss of stability (P = 0.04);Loss of stability (P = 0.04);Loss of stability (P = 0.04);.;

MVP

0.89

ClinPred

1.0

GERP RS

5.0

Varity_R

0.58

gMVP

0.72

Mutation Taster

=4/96

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over