chr2-178677741-TTTCCTCTTCTTCAGGTAGAAC-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4BP6BS2
The NM_001267550.2(TTN):c.34150_34170del(p.Val11384_Glu11390del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000725 in 151,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00073 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0014 ( 9 hom. )
Failed GnomAD Quality Control
Consequence
TTN
NM_001267550.2 inframe_deletion
NM_001267550.2 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.13
Genes affected
TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]
TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM4
?
Nonframeshift variant in NON repetitive region in NM_001267550.2.
BP6
?
Variant 2-178677741-TTTCCTCTTCTTCAGGTAGAAC-T is Benign according to our data. Variant chr2-178677741-TTTCCTCTTCTTCAGGTAGAAC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130665.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=5, Likely_benign=3}. Variant chr2-178677741-TTTCCTCTTCTTCAGGTAGAAC-T is described in Lovd as [Benign]. Variant chr2-178677741-TTTCCTCTTCTTCAGGTAGAAC-T is described in Lovd as [Likely_benign].
BS2
?
High Homozygotes in GnomAdExome at 4 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.34150_34170del | p.Val11384_Glu11390del | inframe_deletion | 146/363 | ENST00000589042.5 | |
LOC124906100 | XR_007087318.1 | n.2185+33271_2185+33291del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.34150_34170del | p.Val11384_Glu11390del | inframe_deletion | 146/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.503-56732_503-56712del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000732 AC: 111AN: 151590Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00133 AC: 330AN: 248956Hom.: 4 AF XY: 0.00163 AC XY: 220AN XY: 135048
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00135 AC: 1979AN: 1460714Hom.: 9 AF XY: 0.00151 AC XY: 1098AN XY: 726634
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GnomAD4 genome ? AF: 0.000725 AC: 110AN: 151708Hom.: 0 Cov.: 31 AF XY: 0.000701 AC XY: 52AN XY: 74160
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 02, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2022 | TTN: BS2 - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 02, 2020 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 20, 2021 | Variant summary: TTN c.30418_30438del21 (p.Val10140_Glu10146del) results in an in-frame deletion that is predicted to remove seven amino acids from the encoded protein. The variant allele was found at a frequency of 0.0013 in 248956 control chromosomes, predominantly at a frequency of 0.0057 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.30418_30438del21 in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1), likely benign (n=4) and benign(n=1). Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 14, 2020 | The p.Val10140_Glu10146del variant in TTN is classified as benign because it has been identified in 0.56% (173/30572) of South Asian chromosomes, including 4 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Arrhythmogenic right ventricular dysplasia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jan 30, 2019 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Genetics and Genomics Program, Sidra Medicine | - | - - |
TTN-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 16, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Jan 22, 2019 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at