rs45491095

Variant names:

• chr16-2062587-G-A
• rs45491095
• NM_000548.5:c.1348G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2062587-G-A
• chr16-2062587-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000548.5(TSC2):​c.1348G>A​(p.Glu450Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E450D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.59
• Publications: 0 publications found

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]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 35 uncertain in NM_000548.5
• 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.1348G>A	p.Glu450Lys	missense_variant	Exon 13 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1348G>A	p.Glu450Lys	missense_variant	Exon 13 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E450K variant (also known as c.1348G>A), located in coding exon 12 of the TSC2 gene, results from a G to A substitution at nucleotide position 1348. The glutamic acid at codon 450 is replaced by lysine, an amino acid with similar properties. This variant was detected in a Greek child with TSC; however, this patient was also found to carry a known splicing c.3814+1G>A mutation in the TSC2 gene. Genetic analysis of the parents of this patient revealed that the father was a carrier of the c.1348G> variant and had no clinical signs of TSC (Papadopoulou A et al. Eur J Paediatr Neurol, 2018 May;22:419-426). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	0.31
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	2.0	M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
PhyloP100		9.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	D;.;.;N;.;D;.;.;N;D;.;.;.;.;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.012	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.017	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.56	P;.;.;.;B;P;.;.;B;B;.;.;.;.;.
Vest4		0.76
MutPred		0.41		Gain of MoRF binding (P = 0.0019);Gain of MoRF binding (P = 0.0019);Gain of MoRF binding (P = 0.0019);.;Gain of MoRF binding (P = 0.0019);Gain of MoRF binding (P = 0.0019);Gain of MoRF binding (P = 0.0019);Gain of MoRF binding (P = 0.0019);.;Gain of MoRF binding (P = 0.0019);Gain of MoRF binding (P = 0.0019);Gain of MoRF binding (P = 0.0019);Gain of MoRF binding (P = 0.0019);Gain of MoRF binding (P = 0.0019);.;
MVP		0.93
ClinPred		0.97	D
GERP RS		5.2
PromoterAI		0.027	Neutral
Varity_R		0.52
gMVP		0.47
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs45491095; hg19: chr16-2112588;