rs1060500913

Variant names:

• chr16-2060718-A-C
• NM_000548.5:c.1024A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-2060718-A-C
• chr16-2060718-A-G
• chr16-2060718-A-T

Variant summary

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

The NM_000548.5(TSC2):​c.1024A>C​(p.Ile342Leu) 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. 13/22 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. I342V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.01

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 rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1024A>C	p.Ile342Leu	missense_variant	Exon 11 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1024A>C	p.Ile342Leu	missense_variant	Exon 11 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isolated focal cortical dysplasia type II Uncertain:1

Aug 03, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I342L variant (also known as c.1024A>C), located in coding exon 10 of the TSC2 gene, results from an A to C substitution at nucleotide position 1024. The isoleucine at codon 342 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is 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	0.15
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.47	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.2	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Benign	0.18
Sift	Uncertain	0.0060	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Benign	0.14	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.88	P;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.54
MutPred		0.43		Loss of MoRF binding (P = 0.1092);Loss of MoRF binding (P = 0.1092);Loss of MoRF binding (P = 0.1092);.;Loss of MoRF binding (P = 0.1092);Loss of MoRF binding (P = 0.1092);Loss of MoRF binding (P = 0.1092);Loss of MoRF binding (P = 0.1092);.;Loss of MoRF binding (P = 0.1092);Loss of MoRF binding (P = 0.1092);Loss of MoRF binding (P = 0.1092);Loss of MoRF binding (P = 0.1092);Loss of MoRF binding (P = 0.1092);.;
MVP		0.54
ClinPred		0.30	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: 8

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: chr16-2110719;