rs587778732

Variant names:

• chr16-2082467-CTGCCAAGGA-G
• rs587778732
• NM_000548.5:c.3846_3855delCTGCCAAGGAinsG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM4 BP6

The NM_000548.5(TSC2):​c.3846_3855delCTGCCAAGGAinsG​(p.Ser1282_Gly1285delinsArg) variant causes a missense, conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1282S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense, conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8 O:1
• Conservation: PhyloP100: 5.83
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000548.5.
• BP6: Variant 16-2082467-CTGCCAAGGA-G is Benign according to our data. Variant chr16-2082467-CTGCCAAGGA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135377.

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.3846_3855delCTGCCAAGGAinsG	p.Ser1282_Gly1285delinsArg	missense conservative_inframe_deletion	Exon 32 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.3843_3852delCTGCCAAGGAinsG	p.Ser1281_Gly1284delinsArg	missense conservative_inframe_deletion	Exon 32 of 42	NP_001393592.1
	TSC2	NM_001406665.1		c.3714_3723delCTGCCAAGGAinsG	p.Ser1238_Gly1241delinsArg	missense conservative_inframe_deletion	Exon 31 of 41	NP_001393594.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.3846_3855delCTGCCAAGGAinsG	p.Ser1282_Gly1285delinsArg	missense conservative_inframe_deletion	Exon 32 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.3814+669_3814+678delCTGCCAAGGAinsG		intron	N/A	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.3682+669_3682+678delCTGCCAAGGAinsG		intron	N/A	ENSP00000384468.2

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 as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Tuberous sclerosis 2 (4)
-	2	1	not provided (3)
-	1	1	not specified (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)
-	-	1	TSC2-related disorder (1)
-	-	1	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=37/163	disease causing

Splicing

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

Other links and lift over

dbSNP: rs587778732; hg19: chr16-2132468; COSMIC: COSV105872618;