chr16-2072981-CAGGT-C

Variant names:

• chr16-2072981-CAGGT-C
• rs137854250
• NM_000548.5:c.2355+2_2355+5delTAGG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_000548.5(TSC2):​c.2355+2_2355+5delTAGG variant causes a splice donor, splice region, intron 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 (★★). ClinVar reports functional evidence for this variant: "SCV003443062: Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID:19259131)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:2
• Conservation: PhyloP100: 9.67
• Publications: 3 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02488938 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.2, offset of 3, new splice context is: gagGTcaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003443062: Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 19259131).; SCV004101301: PCR analysis of cDNA from a patient with the c.2355+2_2355+5del variant demonstrated aberrant splicing that resulted in a premature stop codon (PMID: 19259131).; SCV005876121: in vitro functional analyses demonstrate novel cryptic donor splice site and the generation of a premature stop codon (Le Caignec 2009). PMID: 19259131
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2072981-CAGGT-C is Pathogenic according to our data. Variant chr16-2072981-CAGGT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 12406.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.2355+2_2355+5delTAGG		splice_donor splice_region intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.2355+2_2355+5delTAGG		splice_donor splice_region intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.2355+2_2355+5delTAGG		splice_donor splice_region intron	N/A	NP_001107854.1	P49815-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.2354_2355+2delAGGT	p.Gln785ProfsTer43	frameshift splice_donor splice_region intron	Exon 21 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.2354_2355+2delAGGT	p.Gln785ProfsTer43	frameshift splice_donor splice_region intron	Exon 21 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.2354_2355+2delAGGT	p.Gln785ProfsTer43	frameshift splice_donor splice_region intron	Exon 21 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Tuberous sclerosis 2 (4)
1	-	-	not provided (1)
1	-	-	Tuberous sclerosis syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.47		Position offset: 9
DS_DL_spliceai		0.99		Position offset: 2

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

Other links and lift over

dbSNP: rs137854250; hg19: chr16-2122982;