rs1555497043

Positions:

• chr16-2053424-C-G
• chr16-2053424-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000548.5(TSC2):​c.308C>G​(p.Ala103Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A103A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24582851).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.308C>G	p.Ala103Gly	missense_variant	4/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.308C>G	p.Ala103Gly	missense_variant	4/42	5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 01, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function. This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glycine at codon 103 of the TSC2 protein (p.Ala103Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.0	N;.;.;.;N;N;.;.;N;.;.;N;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.0	N;.;.;N;.;N;.;.;N;.;.;.;.;.;N
REVEL	Uncertain	0.31
Sift	Benign	0.41	T;.;.;T;.;T;.;.;T;.;.;.;.;.;T
Sift4G	Benign	0.34	T;.;.;T;.;T;.;.;T;.;.;.;.;.;T
Polyphen		0.17	B;.;.;.;.;B;.;.;B;.;.;.;.;.;.
Vest4		0.49
MutPred		0.38		Loss of stability (P = 0.0952);Loss of stability (P = 0.0952);Loss of stability (P = 0.0952);.;Loss of stability (P = 0.0952);Loss of stability (P = 0.0952);Loss of stability (P = 0.0952);Loss of stability (P = 0.0952);Loss of stability (P = 0.0952);.;Loss of stability (P = 0.0952);Loss of stability (P = 0.0952);Loss of stability (P = 0.0952);Loss of stability (P = 0.0952);.;
MVP		0.74
ClinPred		0.32	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.17

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: rs1555497043; hg19: chr16-2103425;