rs397515081

Variant names:

• chr16-2050451-A-C
• NM_000548.5:c.190A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-2050451-A-C
• chr16-2050451-A-G
• chr16-2050451-A-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.190A>C​(p.Ile64Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.18

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=0.20671457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.190A>C	p.Ile64Leu	missense_variant	Exon 3 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.190A>C	p.Ile64Leu	missense_variant	Exon 3 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Dec 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 64 of the TSC2 protein (p.Ile64Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1782466). -

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I64L variant (also known as c.190A>C), located in coding exon 2 of the TSC2 gene, results from an A to C substitution at nucleotide position 190. The isoleucine at codon 64 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.46	N;.;.;.;N;N;.;.;N;N;.;.;N;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.20	N;.;.;N;.;N;.;.;N;N;.;.;.;.;.;N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T;.;.;T;.;T;.;.;T;T;.;.;.;.;.;T
Sift4G	Benign	0.88	T;.;.;T;.;T;.;.;T;T;.;.;.;.;.;T
Polyphen		0.86	P;.;.;.;.;B;.;.;P;B;.;.;.;.;.;.
Vest4		0.50
MutPred		0.30		Loss of catalytic residue at M60 (P = 0.0404);Loss of catalytic residue at M60 (P = 0.0404);Loss of catalytic residue at M60 (P = 0.0404);.;Loss of catalytic residue at M60 (P = 0.0404);Loss of catalytic residue at M60 (P = 0.0404);Loss of catalytic residue at M60 (P = 0.0404);Loss of catalytic residue at M60 (P = 0.0404);Loss of catalytic residue at M60 (P = 0.0404);Loss of catalytic residue at M60 (P = 0.0404);Loss of catalytic residue at M60 (P = 0.0404);Loss of catalytic residue at M60 (P = 0.0404);Loss of catalytic residue at M60 (P = 0.0404);Loss of catalytic residue at M60 (P = 0.0404);Loss of catalytic residue at M60 (P = 0.0404);.;
MVP		0.73
ClinPred		0.82	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.34

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: chr16-2100452;