rs137854314

Positions:

• chr16-2080163-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000548.5(TSC2):​c.3401del variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 splice_acceptor
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.06

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.039085545 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: tcctctgccctcttcttcAGggg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2080163-AG-A is Pathogenic according to our data. Variant chr16-2080163-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 50076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2080163-AG-A is described in Lovd as [Pathogenic]. Variant chr16-2080163-AG-A is described in Lovd as [Pathogenic]. Variant chr16-2080163-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3401del		splice_acceptor_variant		ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3401del		splice_acceptor_variant		5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 28, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2013

c.3401delG: p.Gly1134AlafsX57 (G1134AfsX57) in exon 30 of the TSC2 gene (NM_000548.3). Using lowercase to denote intronic nucleotides and uppercase to denote exonic nucleotides, the normal sequence with the base that is deleted in braces is: agGG{G}CCAT.The c.3401delG mutation in the TSC2 gene causes a frameshift starting with codon Glycine 1134, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 57 of the new reading frame, denoted p.Gly1134AlafsX57. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this mutation has not been previously reported to our knowledge, it is considered a disease-causing mutation. The variant is found in EPILEPSY panel(s). -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

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- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 3
DS_AL_spliceai		1.0		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs137854314; hg19: chr16-2130164;