rs137854218
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM4PP3PP5_Very_Strong
The NM_000548.5(TSC2):βc.5238_5255delβ(p.His1746_Arg1751del) variant causes a 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. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: not found (cov: 34)
Exomes π: 6.8e-7 ( 0 hom. )
Consequence
TSC2
NM_000548.5 inframe_deletion
NM_000548.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.73
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM1
In a domain Rap-GAP (size 227) in uniprot entity TSC2_HUMAN there are 284 pathogenic changes around while only 47 benign (86%) in NM_000548.5
PM2
Very rare variant in population databases, with high coverage;
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 [Likely_pathogenic]. Clinvar id is 12402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088292-CCGGCTCCGCCACATCAAG-C is described in Lovd as [Pathogenic]. Variant chr16-2088292-CCGGCTCCGCCACATCAAG-C is described in Lovd as [Likely_pathogenic]. Variant chr16-2088292-CCGGCTCCGCCACATCAAG-C is described in Lovd as [Pathogenic]. Variant chr16-2088292-CCGGCTCCGCCACATCAAG-C is described in Lovd as [Benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TSC2 | NM_000548.5 | c.5238_5255del | p.His1746_Arg1751del | inframe_deletion | 41/42 | ENST00000219476.9 | NP_000539.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TSC2 | ENST00000219476.9 | c.5238_5255del | p.His1746_Arg1751del | inframe_deletion | 41/42 | 5 | NM_000548.5 | ENSP00000219476 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
34
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460560Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726554
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GnomAD4 genome
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:16Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tuberous sclerosis 2 Pathogenic:10
| Pathogenic, criteria provided, single submitter | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | Jul 01, 2023 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2003 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This variant, c.5238_5255del, results in the deletion of 6 amino acid(s) of the TSC2 protein (p.His1746_Arg1751del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with tuberous sclerosis (PMID: 9829910, 10205261, 11112665, 15024740, 15874888, 16114042, 21520333). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12402). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TSC2 function (PMID: 21309039). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tuberous sclerosis-2 (MIM#613254). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical symptoms can vary among affected individuals within the same family (PMID: 31018109). (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic and de novo in multiple individuals with tuberous sclerosis complex (ClinVar, PMID: 32313033). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 25, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University | Jul 17, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region is predicted to change the length of the protein and disrupt normal protein function. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 21309039). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10205261, 11112665). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 10205261). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000012402 / PMID: 9829910/ 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The inframe deletion variant c.5238_5255del (p.His1746_Arg1751del) in TSC2 gene has been reported previously in many individuals with tuberous sclerosis and found to be de novo in several sporadic cases (Rok et al. 2005). Experimental studies have shown that this variant decreases TSC2 expression and activity in vitro (Hoogeveen-Westerveld et al. 2011). The p.His1746_Arg1751del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database with conflicting interpretations of pathogenicity as Pathogenic/Likely Pathogenic. This p.His1746_Arg1751del causes deletion of amino acid Histidine at position 1746 and deletion of amino acid Arginine at position 1751. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province | May 05, 2022 | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 05, 2021 | PP4, PM2, PM4, PM6, PS3, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2022 | TSC2: PM6:Strong, PM1, PM2, PM4, PP4, PS4:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 14, 2023 | This variant appears to occur de novo in multiple individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant decreases TSC2 expression and activity in vitro (PMID 21309039). The variant is located in a region that is considered important for protein function and/or structure. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 16, 2021 | In-frame deletion of 6 amino acids in a non-repeat region; Published functional studies demonstrate a damaging effect, with decreased TSC2 and TSC1 expression and increased S6K phosphorylation (Hoogeveen-Westerveld 2011); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25782670, 5279523, 15121797, 30712878, 26540169, 26563443, 9829910, 22867869, 11112665, 15024740, 10607950, 12752578, 27406250, 29500070, 28397210, 28968464, 31370276, 31591157, 32313033, 32555378, 33942996, 32410215, 32320828, 32091432, 21309039) - |
Tuberous sclerosis syndrome Pathogenic:1Other:2
| not provided, no classification provided | curation | Tuberous sclerosis database (TSC2) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jul 29, 2019 | - - |
| not provided, no classification provided | curation | Tuberous sclerosis database (TSC2) | - | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 08, 2018 | The c.5238_5255del18 pathogenic mutation (also known as p.H1746_R1751del) is located in coding exon 40 of the TSC2 gene. This pathogenic mutation results from an in-frame CATCAAGCGGCTCCGCCA deletion at nucleotide positions 5238 to 5255. This results in the in-frame deletion of six amino acids from codon 1746 to 1751. This deletion was originally reported in a sporadic case with tuberous sclerosis (Beauchamp RL et al. Hum. Mutat., 1998;12:408-16). Subsequently, this mutation (also reported as 5256del18bp and 1746delHIKRLR) has been identified in multiple patients with tuberous sclerosis (Jones AC et al. Am. J. Hum. Genet., 1999 May;64:1305-15; Dabora SL et al. Am. J. Hum. Genet., 2001 Jan;68:64-80; Au KS et al. Genet. Med., 2007 Feb;9:88-100). Furthermore, in vitro analysis showed that the mutant protein (reported as p.1746del6/1723del6) is unstable and increases T389-phosphorylated S6 kinase, thereby preventing the TSC-TSC2-dependent inhibition of the target of rapamycin complex 1 (TORC1) activity (Hoogeveen-Westerveld M et al. Hum. Mutat., 2011 Apr;32:424-35). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis Other:1
| not provided, no classification provided | curation | Tuberous sclerosis database (TSC2) | - | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at