rs45496402

Variant names:

• chr16-2072241-G-A
• rs45496402
• NM_000548.5:c.2098G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2072241-G-A
• chr16-2072241-G-C
• chr16-2072241-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000548.5(TSC2):​c.2098G>A​(p.Glu700Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 15/26 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. E700G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense, splice_region
• Scores: Splicing: ADA: 0.9878
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 9.92
• Publications: 9 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 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.2098G>A	p.Glu700Lys	missense_variant, splice_region_variant	Exon 20 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.2098G>A	p.Glu700Lys	missense_variant, splice_region_variant	Exon 20 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Feb 23, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. SpliceAI prediction score is 0.39 for acceptor loss and the possibility of the variant resulting in abnormal splicing cannot be excluded. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TSC2 related disorder (PMID: 12015165). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Tuberous sclerosis syndrome Other:1

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.99	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.96
MutPred		0.86		Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);.;Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);.;Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);.;
MVP		1.0
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.88
gMVP		0.90
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.39		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45496402; hg19: chr16-2122242;