dbSNP rs768760795: TSC2:p.Ile346Leu (chr16-2060730-A-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4BP6_Moderate

The NM_000548.5(TSC2):c.1036A>C(p.Ile346Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.18

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29745018).

BP6

Variant 16-2060730-A-C is Benign according to our data. Variant chr16-2060730-A-C is described in ClinVar as [Benign]. Clinvar id is 3637184.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.1036A>C	p.Ile346Leu	missense_variant	Exon 11 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.1036A>C	p.Ile346Leu	missense_variant	Exon 11 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251360

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135916

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Benign:1

Apr 11, 2024

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

Benign

0.20

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.53

D;.;.;.;.;.;.;.;.;.;.;.;T;.;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

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

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.30

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

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.8

L;.;.;.;L;L;.;.;.;L;.;L;.;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.8

N;.;.;N;.;N;.;.;N;N;.;.;.;.;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.0060

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

Sift4G

Uncertain

0.022

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

Polyphen

0.88

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

Vest4

0.58

MutPred

0.43

Loss of methylation at K348 (P = 0.0862);Loss of methylation at K348 (P = 0.0862);Loss of methylation at K348 (P = 0.0862);.;Loss of methylation at K348 (P = 0.0862);Loss of methylation at K348 (P = 0.0862);Loss of methylation at K348 (P = 0.0862);Loss of methylation at K348 (P = 0.0862);.;Loss of methylation at K348 (P = 0.0862);Loss of methylation at K348 (P = 0.0862);Loss of methylation at K348 (P = 0.0862);Loss of methylation at K348 (P = 0.0862);Loss of methylation at K348 (P = 0.0862);.;

MVP

0.67

ClinPred

0.57

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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