rs199476153
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_003289.4(TPM2):c.415_417delGAG(p.Glu139del) variant causes a conservative 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
TPM2
NM_003289.4 conservative_inframe_deletion
NM_003289.4 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.01
Genes affected
TPM2 (HGNC:12011): (tropomyosin 2) This gene encodes beta-tropomyosin, a member of the actin filament binding protein family, and mainly expressed in slow, type 1 muscle fibers. Mutations in this gene can alter the expression of other sarcomeric tropomyosin proteins, and cause cap disease, nemaline myopathy and distal arthrogryposis syndromes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
In a chain Tropomyosin beta chain (size 283) in uniprot entity TPM2_HUMAN there are 37 pathogenic changes around while only 3 benign (93%) in NM_003289.4
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_003289.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 9-35685508-TCTC-T is Pathogenic according to our data. Variant chr9-35685508-TCTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 12465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35685508-TCTC-T is described in Lovd as [Pathogenic]. Variant chr9-35685508-TCTC-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital myopathy 23 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 04, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Mar 06, 2024 | PS3, PM1, PM2, PM4, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 12465). This variant has been previously reported as causative for congenital myopathy (PMID:24507666). - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 28, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 07, 2022 | Variant summary: TPM2 c.415_417delGAG (p.Glu139del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 251480 control chromosomes. c.415_417delGAG has been reported in the literature in multiple individuals affected with Nemaline Myopathy 4 (Cap myopathy) (example, Lehtokari_2007, Clarke_2009, Tasca_2013, Citirak_2014). Some of the ascertained reports indicated a de-novo origin and at-least once instance of somatic mosaicism resulting in a milder presentation has been reported (example, Tasca_2013). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence that the mutant protein incorporates into sarcomeric structures, where it likely imposes a dominant-negative effect to cause muscle weakness (example, Clarke_2009) and increased myofibrillar calcium sensitivity consistent with a gain of function mechanism (example, Marston_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | TPM2 homepage - Leiden Muscular Dystrophy pages | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2023 | TPM2: PS2, PM2, PS3:Moderate, PS4:Moderate - |
Arthrogryposis, distal, type 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 04, 2020 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this in-frame deletion causes increased calcium sensitivity and inhibits myosin binding (PMID: 23886664, 25978979). This variant has been reported in multiple unrelated individuals affected with autosomal dominant cap myopathy and nemaline myopathy (PMID: 17434307, 23015096, 24692096, 25127990), including several affected individuals where it arose de novo (PMID: 19345583, 24507666). ClinVar contains an entry for this variant (Variation ID: 12465). This variant is not present in population databases (ExAC no frequency). This variant, c.415_417del, results in the deletion of 1 amino acid of the TPM2 protein (p.Glu139del), but otherwise preserves the integrity of the reading frame. - |
TPM2-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 15, 2024 | The TPM2 c.415_417delGAG variant is predicted to result in an in-frame deletion (p.Glu139del). This variant was reported in numerous individuals with nemaline myopathy or CAP myopathy (Lehtokari et al. 2007. PubMed ID: 17434307; Marttila et al. 2014. PubMed ID: 24692096; Table S1, Westra et al. 2019. PubMed ID: 31127727; Supplementary data, Gonzalez-Quereda et al. 2020. PubMed ID: 32403337). Functional studies showed that this variant impacts normal protein function (Marttila et al. 2012. PubMed ID: 22084935; Marston et al. 2013. PubMed ID: 23886664; Borovikov et al. 2015. PubMed ID: 25978979). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at