rs1060504103

Positions:

• chr16-2065552-C-G
• chr16-2065552-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.1633C>G​(p.Leu545Val) 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. 12/20 in silico tools predict 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. L545P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.941

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=0.12015939).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.1633C>G	p.Leu545Val	missense_variant	16/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.1633C>G	p.Leu545Val	missense_variant	16/42	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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2023	This variant has not been reported in the literature in individuals affected with TSC2-related conditions. 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. ClinVar contains an entry for this variant (Variation ID: 819714). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 545 of the TSC2 protein (p.Leu545Val). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2019

The p.L545V variant (also known as c.1633C>G), located in coding exon 15 of the TSC2 gene, results from a C to G substitution at nucleotide position 1633. The leucine at codon 545 is replaced by valine, an amino acid with highly similar properties. This amino acid position is 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	19
DANN	Benign	0.26
DEOGEN2	Benign	0.37	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.019	D
MutationAssessor	Benign	1.1	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster	Benign	0.85	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.42	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.52
Sift	Benign	0.59	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.69	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.98	D;.;.;.;B;P;.;.;B;B;.;.;.;.;.
Vest4		0.48
MutPred		0.19		Loss of glycosylation at P543 (P = 0.1273);Loss of glycosylation at P543 (P = 0.1273);Loss of glycosylation at P543 (P = 0.1273);.;Loss of glycosylation at P543 (P = 0.1273);Loss of glycosylation at P543 (P = 0.1273);Loss of glycosylation at P543 (P = 0.1273);Loss of glycosylation at P543 (P = 0.1273);.;Loss of glycosylation at P543 (P = 0.1273);Loss of glycosylation at P543 (P = 0.1273);Loss of glycosylation at P543 (P = 0.1273);Loss of glycosylation at P543 (P = 0.1273);Loss of glycosylation at P543 (P = 0.1273);.;
MVP		0.88
ClinPred		0.067	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.072
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1060504103; hg19: chr16-2115553;