rs137854880

Positions:

• chr16-2085322-G-A
• chr16-2085322-G-C
• chr16-2085322-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000548.5(TSC2):​c.4662G>A​(p.Gln1554Gln) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: TSC2 NM_000548.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 9.66

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 4: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, phyloP100way_vertebrate [when BayesDel_noAF, Dann was below the threshold]
• PP5: Variant 16-2085322-G-A is Pathogenic according to our data. Variant chr16-2085322-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 49485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2085322-G-A is described in Lovd as [Pathogenic]. Variant chr16-2085322-G-A is described in Lovd as [Likely_pathogenic]. Variant chr16-2085322-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4662G>A	p.Gln1554Gln	splice_region_variant, synonymous_variant	36/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4662G>A	p.Gln1554Gln	splice_region_variant, synonymous_variant	36/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Pathogenic:1 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	The c.4662G>A (p.Gln1554=) variant in the TSC2 gene is a synonymous variant located at the last nucleotide of exon 36, which is part of the consensus splice site for this exon. This nucleotide substitution is predicted to affect normal splicing (SpliceAI donor loss score: 0.65 at the canonical donor splice site, and donor gain score: 0.5 at 23 nucleotides downstream). To our knowledge, functional studies demonstrating the impact of this variant on RNA splicing have not been reported for this variant. This variant has been reported in at least four individuals affected with tuberous sclerosis, with de novo occurrence reported in three individuals (ClinVar ID: 49485 (SCV001396837.5, SCV000066540.3); LOVD). This variant is absent in the general population according to gnomAD. Therefore, c.4662G>A (p.Gln1554=) variant in TSC2 gene is classified as pathogenic. -

Tuberous sclerosis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2019

For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed to be de novo in an individual affected with tuberous sclerosis (Invitae). ClinVar contains an entry for this variant (Variation ID: 49485). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 1554 of the TSC2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TSC2 protein. This variant also falls at the last nucleotide of exon 36 of the TSC2 coding sequence, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	23
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.50		Position offset: 23
DS_DL_spliceai		0.65		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs137854880; hg19: chr16-2135323;