rs45517111

Positions:

• chr16-2055416-C-A
• chr16-2055416-C-T

Variant summary

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

The NM_000548.5(TSC2):​c.496C>A​(p.Gln166Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.496C>A	p.Gln166Lys	missense_variant	6/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.496C>A	p.Gln166Lys	missense_variant	6/42	5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Jun 09, 2023

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 166 of the TSC2 protein (p.Gln166Lys). 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 disrupt the consensus splice site. 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 (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.30
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	Uncertain	0.24	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.7	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.61
Sift	Benign	0.29	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.19	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.93	P;.;.;.;.;P;.;.;D;P;.;.;.;.;.
Vest4		0.73
MutPred		0.57		Gain of ubiquitination at Q166 (P = 0.0162);Gain of ubiquitination at Q166 (P = 0.0162);Gain of ubiquitination at Q166 (P = 0.0162);.;Gain of ubiquitination at Q166 (P = 0.0162);Gain of ubiquitination at Q166 (P = 0.0162);Gain of ubiquitination at Q166 (P = 0.0162);Gain of ubiquitination at Q166 (P = 0.0162);.;Gain of ubiquitination at Q166 (P = 0.0162);Gain of ubiquitination at Q166 (P = 0.0162);Gain of ubiquitination at Q166 (P = 0.0162);Gain of ubiquitination at Q166 (P = 0.0162);Gain of ubiquitination at Q166 (P = 0.0162);.;
MVP		0.86
ClinPred		0.74	D
GERP RS		4.8
Varity_R		0.38
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2105417;