rs189951108
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6
The NM_001267550.2(TTN):c.21548G>A(p.Cys7183Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 1,613,390 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.21548G>A | p.Cys7183Tyr | missense_variant | 74/363 | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.21548G>A | p.Cys7183Tyr | missense_variant | 74/363 | 5 | NM_001267550.2 | P1 | |
ENST00000590024.1 | n.96C>T | non_coding_transcript_exon_variant | 1/1 | ||||||
TTN-AS1 | ENST00000659121.1 | n.503-10952C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000473 AC: 72AN: 152110Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000415 AC: 103AN: 248348Hom.: 0 AF XY: 0.000475 AC XY: 64AN XY: 134750
GnomAD4 exome AF: 0.000747 AC: 1092AN: 1461162Hom.: 1 Cov.: 33 AF XY: 0.000729 AC XY: 530AN XY: 726840
GnomAD4 genome ? AF: 0.000473 AC: 72AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30AN XY: 74426
ClinVar
Submissions by phenotype
not provided Uncertain:7Benign:4
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, 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 | GeneDx | Nov 06, 2020 | This variant is associated with the following publications: (PMID: 23861362, 28771489) - |
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 | Revvity Omics, Revvity | Oct 05, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 19, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 04, 2021 | The TTN c.21548G>A; p.Cys7183Tyr variant (rs189951108; ClinVar Variation ID: 178242) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Cys7183Tyr variant cannot be determined with certainty. Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 22, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 10, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 12, 2017 | The p.Cys5939Tyr variant in TTN has been identified by our laboratory in 1 indiv idual with RCM and 1 with HCM; however, both individuals harbor pathogenic varia nts in other genes responsible for their symptoms. This variant has been identif ied in 76/126152 of European chromosomes by the Genome Aggregation Database (gno mAD, http://gnomad.broadinstitute.org/; dbSNP rs189951108) and has been reported in ClinVar (Variation ID: 178242). Computational prediction tools and conservat ion analysis suggest that the p.Cys5939Tyr variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, the clinical significance of the p.Cys5939Tyr variant is uncertain. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2017 | - - |
TTN-related condition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 25, 2023 | The TTN c.21548G>A variant is predicted to result in the amino acid substitution p.Cys7183Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.060% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179588279-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Arrhythmogenic right ventricular 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 | Apr 09, 2019 | - - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 16, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at