Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_001267550.2(TTN):āc.36347A>Gā(p.Glu12116Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,613,386 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
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]
PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, TTN
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.006957084).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-178664032-T-C is Benign according to our data. Variant chr2-178664032-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 192216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178664032-T-C is described in Lovd as [Benign]. Variant chr2-178664032-T-C is described in Lovd as [Likely_benign].
BS1
?
BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00206 (313/152278) while in subpopulation NFE AF= 0.00379 (258/68008). AF 95% confidence interval is 0.00341. There are 0 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
?
BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Likely benign, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Apr 21, 2022
- -
Likely benign, no assertion criteria provided
clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
-
- -
Likely benign, no assertion criteria provided
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
-
- -
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Aug 01, 2023
TTN: BP4 -
Likely benign, no assertion criteria provided
clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht
-
- -
not specified Benign:3
Benign, no assertion criteria provided
clinical testing
Clinical Genetics, Academic Medical Center
-
- -
Benign, criteria provided, single submitter
research
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Jun 24, 2013
- -
Benign, no assertion criteria provided
clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
-
- -
Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Sep 10, 2021
- -
TTN-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Oct 12, 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
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Jan 25, 2016
- -
Early-onset myopathy with fatal cardiomyopathy Benign:1
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Sep 10, 2021
- -
Tibial muscular dystrophy Benign:1
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Sep 10, 2021
- -
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1