rs137854123

Positions:

• chr16-2056731-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PP3_Moderate BS2

The NM_000548.5(TSC2):​c.736A>G​(p.Thr246Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,624 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).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2 O:1
• Conservation: PhyloP100: 9.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 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, 15 uncertain in NM_000548.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.736A>G	p.Thr246Ala	missense_variant	8/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.736A>G	p.Thr246Ala	missense_variant	8/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249706 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135136

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459624 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000299 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:2 Other:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces threonine with alanine at codon 246 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with tuberous sclerosis complex (PMID: 18772611). This variant has been identified in 4/249706 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Tuberous sclerosis 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 21, 2016

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr246Ala variant in TSC2 has been reported in 1 Asian individual as well as one family m ember with Tuberous Sclerosis (Sasongko 2008). This variant has been identified in 1/10372 African chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs137854123). Computational prediction tools and conservation analysis suggest that the p.Thr246Ala variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Thr246Ala variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 30, 2022

Previously reported as a maternally inherited variant of uncertain significance in a patient suspected to have TSC; detailed clinical information not provided (Meng et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18466115, 26994145, 30564305, 18772611, 32917966, 25637381) -

Isolated focal cortical dysplasia type II Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 17, 2023

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The p.T246A variant (also known as c.736A>G), located in coding exon 7 of the TSC2 gene, results from an A to G substitution at nucleotide position 736. The threonine at codon 246 is replaced by alanine, an amino acid with similar properties. This alteration was detected in two members of a Japanese family with features of tuberous sclerosis (TSC) (Sasongko TH et al, 2008 May;54:E73-81). This alteration was identified in 1/374 Chinese patients with clinically suspected TSC undergoing genetic testing within the TSC1 and TSC2 genes, and was classified as a variant of unknown significance by the authors (Meng Y et al. J Hum Genet, 2021 Mar;66:227-236). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.5	M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.4	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0070	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.0090	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.99	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.87
MVP		0.95
ClinPred		0.73	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.56

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

Other links and lift over

dbSNP: rs137854123; hg19: chr16-2106732;