rs143537386

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PM1PM2BP6_Very_Strong

The NM_000548.5(TSC2):c.2565C>A(p.His855Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H855P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.245

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: 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: Likely_benign. The variant received -4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 35 uncertain in NM_000548.5

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 16-2075818-C-A is Benign according to our data. Variant chr16-2075818-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 663457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.2565C>A	p.His855Gln	missense_variant	Exon 23 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.2565C>A	p.His855Gln	missense_variant	Exon 23 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250298

AF XY:

0.00000737

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:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Benign:1

Jul 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Jan 31, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.79

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

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.81

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.72

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

M_CAP

Pathogenic

0.39

MetaRNN

Uncertain

0.47

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.048

MutationAssessor

Uncertain

2.6

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

PhyloP100

0.24

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.2

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

REVEL

Uncertain

0.62

Sift

Benign

0.13

T;.;.;T;.;T;.;.;T;T;.;.;.;.;T

Sift4G

Benign

0.067

T;.;.;T;.;T;.;.;T;T;.;.;.;.;T

Polyphen

0.0010

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

Vest4

0.37

MutPred

0.47

Loss of methylation at R852 (P = 0.2363);Loss of methylation at R852 (P = 0.2363);Loss of methylation at R852 (P = 0.2363);.;Loss of methylation at R852 (P = 0.2363);Loss of methylation at R852 (P = 0.2363);Loss of methylation at R852 (P = 0.2363);Loss of methylation at R852 (P = 0.2363);.;Loss of methylation at R852 (P = 0.2363);Loss of methylation at R852 (P = 0.2363);Loss of methylation at R852 (P = 0.2363);Loss of methylation at R852 (P = 0.2363);Loss of methylation at R852 (P = 0.2363);.;

MVP

0.90

ClinPred

0.60

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.38

Mutation Taster

=31/69

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over