Variant rs143537386 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP6_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 (★★). Synonymous variant affecting the same amino acid position (i.e. H855H) 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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

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 [Likely_benign]. Clinvar id is 663457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.2565C>A	p.His855Gln	missense_variant	23/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.2565C>A	p.His855Gln	missense_variant	23/42	5	NM_000548.5	ENSP00000219476		P49815-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250298

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135740

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 SAS 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

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

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;.;.;.

MutationTaster

Benign

1.0

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over