NM_000548.5:c.1283_1285delCCT

Variant names:

• chr16-2062519-TCTC-T
• rs137853983
• NM_000548.5:c.1283_1285delCCT

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PM4_Supporting PP5_Very_Strong

The NM_000548.5(TSC2):​c.1283_1285delCCT​(p.Ser428del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000243731: Published functional studies demonstrate a damaging effect on TSC complex formation and TSC complex dependent inhibition of mTORC1 activity (Rosengren et al., 2020" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S428S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.59
• 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: 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000243731: Published functional studies demonstrate a damaging effect on TSC complex formation and TSC complex dependent inhibition of mTORC1 activity (Rosengren et al., 2020; TSC2 LOVD); SCV001471649: Functional evaluation in heterologous cell culture indicates this variant disrupts TSC complex activity as measured by increased downstream mTOR activity (Rosengren 2020).; SCV000544460: Experimental studies have shown that this variant affects TSC2 function (PMID: 32555378).; SCV004116495: "In vitro functional studies suggest this variant leads to disrupted TSC-complex function (Figure 2, Table 3, Rosengren et al. 2020. PubMed ID: 32555378)."
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000548.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 16-2062519-TCTC-T is Pathogenic according to our data. Variant chr16-2062519-TCTC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 49644.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.1283_1285delCCT	p.Ser428del	disruptive_inframe_deletion	Exon 13 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.1283_1285delCCT	p.Ser428del	disruptive_inframe_deletion	Exon 13 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.1283_1285delCCT	p.Ser428del	disruptive_inframe_deletion	Exon 13 of 41	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.1283_1285delCCT	p.Ser428del	disruptive_inframe_deletion	Exon 13 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.1283_1285delCCT	p.Ser428del	disruptive_inframe_deletion	Exon 13 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.1283_1285delCCT	p.Ser428del	disruptive_inframe_deletion	Exon 13 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/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Tuberous sclerosis 2 (2)
1	-	-	TSC2-related disorder (1)
-	-	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=72/28	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs137853983; hg19: chr16-2112520;