chr16-2084328-G-A

Position:

chr16-2084328-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000548.5(TSC2):c.4106G>A(p.Arg1369Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign 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. R1369W) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3O:1

Conservation

PhyloP100: 2.83

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 Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18717614).

BP6

Variant 16-2084328-G-A is Benign according to our data. Variant chr16-2084328-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135386.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, not_provided=1, Uncertain_significance=2}.

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.4106G>A	p.Arg1369Gln	missense_variant	34/42	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.4106G>A	p.Arg1369Gln	missense_variant	34/42	5	NM_000548.5	ENSP00000219476		P49815-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

248622

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135142

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460376

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726478

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jan 08, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 16, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 30, 2023	The p.R1369Q variant (also known as c.4106G>A), located in coding exon 33 of the TSC2 gene, results from a G to A substitution at nucleotide position 4106. The arginine at codon 1369 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well 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. -

TSC2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2024

The TSC2 c.4106G>A variant is predicted to result in the amino acid substitution p.Arg1369Gln. This variant was reported in an individual with autism spectrum disorder (Table S3, Saskin et al. 2017. PubMed ID: 28250423; g.2074330 hg18 in Table 1, Schaaf et al. 2011. PubMed: 21624971). However, the variant was also reported in a healthy control (g.2134329 hg19 in Table S1, Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations ranging from uncertain to benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135386/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

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

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.061

MetaRNN

Benign

0.19

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

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

0.64

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

MutationTaster

Benign

0.71

N;N;N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.44

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

REVEL

Uncertain

0.46

Sift

Benign

0.19

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

Sift4G

Benign

0.50

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

Polyphen

0.72

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

Vest4

0.33

MVP

0.94

ClinPred

0.066

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.065

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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