16-2088030-A-G

Variant names:

• chr16-2088030-A-G
• rs45484794
• NM_000548.5:c.5069-18A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000548.5(TSC2):​c.5069-18A>G variant causes a intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). There are indicators that this mutation may affect the branch point..

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 3.96
• Publications: 1 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2088030-A-G is Pathogenic according to our data. Variant chr16-2088030-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 49345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.5069-18A>G		intron	N/A	NP_000539.2
	TSC2	NM_001406663.1		c.5066-18A>G		intron	N/A	NP_001393592.1
	TSC2	NM_001114382.3		c.5000-18A>G		intron	N/A	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.5069-18A>G		intron	N/A	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.5000-18A>G		intron	N/A	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.4868-18A>G		intron	N/A	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Pathogenic:1 Other:1

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tuberous sclerosis 2 Pathogenic:1

Oct 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in multiple mRNA products and introduces a premature termination codon (PMID: 10533066, 11068191). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 49345). This variant is also known as IVS38-18A>G. This variant has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 10533066, 21520333; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 39 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.47
PhyloP100		4.0
La Branchor		0.88
BranchPoint Hunter		5.0
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.38		Position offset: 18

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

Other links and lift over

dbSNP: rs45484794; hg19: chr16-2138031;