rs1555498839

chr16-2056693-C-Gchr16-2056693-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000548.5(TSC2):c.698C>G(p.Ala233Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A233S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3391158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.698C>G	p.Ala233Gly	missense_variant	8/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.698C>G	p.Ala233Gly	missense_variant	8/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Invitae

Jul 20, 2017

This variant has not been reported in the literature in individuals with TSC2-related disease. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glycine at codon 233 of the TSC2 protein (p.Ala233Gly). 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	0.13
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	0.063
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.0	N;.;.;.;N;N;.;.;.;N;.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.1	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.41
Sift	Benign	0.18	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Uncertain	0.023	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.36	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.55
MutPred		0.47		Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);.;Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);.;Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);.;
MVP		0.68
ClinPred		0.82	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.097

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.41		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555498839; hg19: chr16-2106694;