chr17-39665391-CGGA-C
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_SupportingBP6BS1
The NM_003673.4(TCAP):c.37_39del(p.Glu13del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00119 in 1,613,638 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S11S) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00095 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 1 hom. )
Consequence
TCAP
NM_003673.4 inframe_deletion
NM_003673.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.92
Genes affected
TCAP (HGNC:11610): (titin-cap) Sarcomere assembly is regulated by the muscle protein titin. Titin is a giant elastic protein with kinase activity that extends half the length of a sarcomere. It serves as a scaffold to which myofibrils and other muscle related proteins are attached. This gene encodes a protein found in striated and cardiac muscle that binds to the titin Z1-Z2 domains and is a substrate of titin kinase, interactions thought to be critical to sarcomere assembly. Mutations in this gene are associated with limb-girdle muscular dystrophy type 2G. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_003673.4. Strenght limited to Supporting due to length of the change: 1aa.
BP6
Variant 17-39665391-CGGA-C is Benign according to our data. Variant chr17-39665391-CGGA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44707.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Uncertain_significance=1, Benign=5}. Variant chr17-39665391-CGGA-C is described in Lovd as [Likely_benign]. Variant chr17-39665391-CGGA-C is described in Lovd as [Benign]. Variant chr17-39665391-CGGA-C is described in Lovd as [Pathogenic]. Variant chr17-39665391-CGGA-C is described in Lovd as [Likely_pathogenic].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000947 (144/152134) while in subpopulation NFE AF= 0.00153 (104/67986). AF 95% confidence interval is 0.00129. There are 0 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TCAP | NM_003673.4 | c.37_39del | p.Glu13del | inframe_deletion | 1/2 | ENST00000309889.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TCAP | ENST00000309889.3 | c.37_39del | p.Glu13del | inframe_deletion | 1/2 | 1 | NM_003673.4 | P1 | |
TCAP | ENST00000578283.1 | c.37_39del | p.Glu13del | inframe_deletion | 1/3 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000947 AC: 144AN: 152016Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00100 AC: 251AN: 251088Hom.: 1 AF XY: 0.00101 AC XY: 137AN XY: 135822
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GnomAD4 exome AF: 0.00122 AC: 1776AN: 1461504Hom.: 1 AF XY: 0.00123 AC XY: 891AN XY: 727068
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GnomAD4 genome AF: 0.000947 AC: 144AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.000793 AC XY: 59AN XY: 74360
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:15
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:5
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 02, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 10, 2019 | The p.Glu13del variant in TCAP is classified as benign because it has been identified in 0.4% (43/10340) of Ashkenazi Jewish chromosomes (including one homozygote) and in 0.1% (182/128862) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 19, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Apr 20, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 03, 2018 | Variant summary: TCAP c.37_39delGAG (p.Glu13del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 0.001 in 276952 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 40-fold of the estimated maximal expected allele frequency for a pathogenic variant in TCAP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. The variant, c.37_39delGAG, has been reported in the literature in individuals affected with Cardiomyopathy as well as in controls (Marziliano_2006, Perrot_2006). In vitro studies have shown the variant to result in the inability to bind the titin N-terminus due to the loss of proper formation of the telethonin B-hairpin structure, which the authors state may in fact be harmless (Knoll_2011). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. One cardiology center (via ClinVar), reports the variant in HCM family members who also carried a pathogenic MYBPC3 variant, and in another family, the variant did not segregate with disease in all affected family members. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2014 | The variant is found in DCM,CARDIOMYOPATHY panel(s). - |
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 03, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | TCAP: PM4:Supporting, BS2 - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 08, 2018 | - - |
Long QT syndrome Benign:1
Benign, criteria provided, single submitter | research | Dept of Medical Biology, Uskudar University | Jan 08, 2024 | Criteria: BS1, BS2, PM4 - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 06, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Hypertrophic cardiomyopathy 25 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Hypertrophic cardiomyopathy 1 Benign:1
Benign, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Mar 16, 2017 | The TCAP Glu13del variant has been previously identified in multiple HCM and DCM patients (Bos JM, et al., 2006; Perrot A, et al., 2006; Marziliano N, et al., 2006; Anderson PS, et al., 2009; Hirtle-Lewis M, et al., 2013; Pugh TJ, et al., 2014), however it has also been identified control cohorts at an allele frequency of up to 0.5% (Perrot A, et al., 2006; Marziliano N, et al., 2006; Anderson PS, et al., 2009). In vitro functional evaluations have shown that the TCAP Glu13del variant causes improper formation of telethonin β-hairpin structure necessary for titin binding, that may in fact be harmless (Knoll R, et al., 2011). The variant is present in the Exome Aggregation Consortium dataset (MAF= 0.00095; http://exac.broadinstitute.org/). We identified this variant in 3 HCM probands. In one of these families both the proband and an affected family member also carried a second pathogenic variant (MYBPC3 p.Pro955Argfs*95). In another family it was found to cosegregate in two affected family members, but did not segregate to a third affected family member. In summary, based on identification of the variant in controls, high allele frequency, as well as the lack of segregation in our family, we classify TCAP Glu13del as a "benign" variant. - |
Computational scores
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Details are displayed if max score is > 0.2
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