rs1555512887

Variant names:

• chr16-2082501-G-GC
• rs1555512887
• NM_000548.5:c.3881dupC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 10P and 2B. PVS1 PM2 BP6_Moderate

The NM_000548.5(TSC2):​c.3881dupC​(p.Asp1295ArgfsTer27) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TSC2 NM_000548.5 frameshift, splice_region
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.13
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-2082501-G-GC is Benign according to our data. Variant chr16-2082501-G-GC is described in ClinVar as Likely_benign. ClinVar VariationId is 535956.Status of the report is criteria_provided_single_submitter, 1 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.3881dupC	p.Asp1295ArgfsTer27	frameshift splice_region	Exon 32 of 42	NP_000539.2
	TSC2	NM_001406665.1		c.3749dupC	p.Gly1251ArgfsTer45	frameshift	Exon 31 of 41	NP_001393594.1
	TSC2	NM_001406663.1		c.3878dupC	p.Asp1294ArgfsTer27	frameshift splice_region	Exon 32 of 42	NP_001393592.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.3881dupC	p.Asp1295ArgfsTer27	frameshift splice_region	Exon 32 of 42	ENSP00000219476.3
	TSC2	ENST00000439117.6	TSL:1	n.*3048dupC		splice_region non_coding_transcript_exon	Exon 28 of 38	ENSP00000406980.2
	TSC2	ENST00000439117.6	TSL:1	n.*3048dupC		3_prime_UTR	Exon 28 of 38	ENSP00000406980.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1555512887; hg19: chr16-2132502;