NM_000548.5:c.5238_5255delCATCAAGCGGCTCCGCCA

Variant names:

• chr16-2088292-CCGGCTCCGCCACATCAAG-C
• rs137854218
• NM_000548.5:c.5238_5255delCATCAAGCGGCTCCGCCA

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM4 PP3 PP5_Very_Strong

The NM_000548.5(TSC2):​c.5238_5255delCATCAAGCGGCTCCGCCA​(p.His1746_Arg1751del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,560 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H1746H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC2 NM_000548.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 O:3
• Conservation: PhyloP100: 9.73
• Publications: 7 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 13 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 35 uncertain in NM_000548.5
• PM4: Nonframeshift variant in NON repetitive region in NM_000548.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 16-2088292-CCGGCTCCGCCACATCAAG-C is Pathogenic according to our data. Variant chr16-2088292-CCGGCTCCGCCACATCAAG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12402.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.5238_5255delCATCAAGCGGCTCCGCCA	p.His1746_Arg1751del	disruptive_inframe_deletion	Exon 41 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.5235_5252delCATCAAGCGGCTCCGCCA	p.His1745_Arg1750del	disruptive_inframe_deletion	Exon 41 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.5169_5186delCATCAAGCGGCTCCGCCA	p.His1723_Arg1728del	disruptive_inframe_deletion	Exon 40 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.5238_5255delCATCAAGCGGCTCCGCCA	p.His1746_Arg1751del	disruptive_inframe_deletion	Exon 41 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.5169_5186delCATCAAGCGGCTCCGCCA	p.His1723_Arg1728del	disruptive_inframe_deletion	Exon 40 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.5037_5054delCATCAAGCGGCTCCGCCA	p.His1679_Arg1684del	disruptive_inframe_deletion	Exon 39 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460560 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726554

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Tuberous sclerosis 2 (10)
4	-	-	not provided (4)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Tuberous sclerosis syndrome (3)
-	-	-	Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

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

Other links and lift over

dbSNP: rs137854218; hg19: chr16-2138293; COSMIC: COSV51911473;