chr2-178745884-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_133379.5(TTN):c.16516G>T(p.Glu5506*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000839 in 1,609,784 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_133379.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_133379.5 | c.16516G>T | p.Glu5506* | stop_gained | Exon 46 of 46 | ENST00000360870.10 | NP_596870.2 | |
TTN | NM_001267550.2 | c.11312-3963G>T | intron_variant | Intron 47 of 362 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000360870.10 | c.16516G>T | p.Glu5506* | stop_gained | Exon 46 of 46 | 5 | NM_133379.5 | ENSP00000354117.4 | ||
TTN | ENST00000589042.5 | c.11312-3963G>T | intron_variant | Intron 47 of 362 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151888Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000608 AC: 15AN: 246836Hom.: 0 AF XY: 0.0000600 AC XY: 8AN XY: 133320
GnomAD4 exome AF: 0.0000878 AC: 128AN: 1457896Hom.: 1 Cov.: 33 AF XY: 0.0000855 AC XY: 62AN XY: 725112
GnomAD4 genome AF: 0.0000461 AC: 7AN: 151888Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74156
ClinVar
Submissions by phenotype
not specified Uncertain:2
Variant classified as Uncertain Significance - Favor Benign. The p.Glu5506X variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 5/8598 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs148430495). This variant is located in the last exon of an alternative transcript (Novex-3) and is expected to result in a truncated protein. Although truncating variants in the TTN gene are common in individuals with DCM (Herman 2012), the role of the Novex-3 transcript in cardiomyopathy is unclear. In summary, additional information is needed to fully assess the clinical significance of the Glu5506X variant. -
Variant summary: TTN NM_133378:c.10360+7240G>T is located at a position not widely known to affect splicing. This variant corresponds to c.11312-3963G>T in NM_001267550 and NM_133379:c.16516G>T p.Glu5506X, however nonsense mediated decay is not expected. Loss of function variants in all TTN bands are strongly associated with a spectrum of autosomal recessive titinopathies when exon expression (proportion spliced in, PSI, 1=complete expression) in skeletal muscle is >0.1 (PMID: 36977548, 39198997, 29598826, 32778822, 29691892, 33449170, 36977548, internal data). In contrast, loss of function variants in all TTN bands are only strongly associated with autosomal dominant TTN-related cardiomyopathies if located in exons constitutively expressed (PSI >0.9) in cardiac muscle, excluding extreme C-terminal exons 359-363 (PMID: 25589632, 31216868, 32964742, 34662387, 27869827, Shetty et al., Nat Cardiovasc Res 2024, cardiodb.org, internal data). This variant has a maximum skeletal muscle PSI of 0.02 and a maximum cardiac muscle PSI of 0.035. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.4e-05 in 330022 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Autosomal Recessive Titinopathy (6.4e-05 vs 0.00039), allowing no conclusion about variant significance. c.10360+7240G>T has been reported in the literature in individuals affected with clinical features of cardiomyopathy without strong evidence for causality (Jurgens_2022) and wad not enriched in the Atrial Fibrillation cohort from the UK Biobank (Connell_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Titinopathy and other TTN-related diseaes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31691645, 35177841, 33226272). ClinVar contains an entry for this variant (Variation ID: 166247). Based on the evidence outline above, and the lack of clinical evidence in a low PSI exon, the variant has been classified as uncertain significance. -
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Uncertain:1
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not provided Uncertain:1
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Tibial muscular dystrophy Uncertain:1
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply. -
Primary dilated cardiomyopathy Uncertain:1
This TTN truncating variant (TTNtv) was identified in three individuals in this cohort. It affects only the Novex-3 isoform, which does not span the sarcomere and has not been implicated in DCM. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at