NM_000548.5:c.4552A>C

Variant names:

• chr16-2085009-A-C
• NM_000548.5:c.4552A>C

Variant summary

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

The NM_000548.5(TSC2):​c.4552A>C​(p.Ile1518Leu) 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 (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

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=0.1671192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4552A>C	p.Ile1518Leu	missense_variant	Exon 35 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4552A>C	p.Ile1518Leu	missense_variant	Exon 35 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I1518L variant (also known as c.4552A>C), located in coding exon 34 of the TSC2 gene, results from an A to C substitution at nucleotide position 4552. The isoleucine at codon 1518 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	14
DANN	Benign	0.65
DEOGEN2	Benign	0.38	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.37	N;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.090	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.46
Sift	Benign	0.79	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	1.0	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.0010	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.40
MutPred		0.35		Loss of methylation at K1516 (P = 0.0554);.;.;.;.;.;.;Loss of methylation at K1516 (P = 0.0554);.;.;.;.;.;.;.;
MVP		0.79
ClinPred		0.058	T
GERP RS		3.0
Varity_R		0.28
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: chr16-2135010;