2-178746072-A-G
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_133379.5(TTN):āc.16328T>Cā(p.Val5443Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000424 in 1,613,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 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_133379.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_133379.5 | c.16328T>C | p.Val5443Ala | missense_variant | Exon 46 of 46 | ENST00000360870.10 | NP_596870.2 | |
TTN | NM_001267550.2 | c.11312-4151T>C | 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.16328T>C | p.Val5443Ala | missense_variant | Exon 46 of 46 | 5 | NM_133379.5 | ENSP00000354117.4 | ||
TTN | ENST00000589042.5 | c.11312-4151T>C | intron_variant | Intron 47 of 362 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes AF: 0.000414 AC: 63AN: 152000Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000348 AC: 87AN: 250316Hom.: 0 AF XY: 0.000281 AC XY: 38AN XY: 135234
GnomAD4 exome AF: 0.000425 AC: 621AN: 1461328Hom.: 0 Cov.: 33 AF XY: 0.000399 AC XY: 290AN XY: 726982
GnomAD4 genome AF: 0.000414 AC: 63AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29AN XY: 74386
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4
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TTN-related myopathy Uncertain:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is known mechanism of disease in this gene. In addition, dominant-negative is also a suggested mechanism as not all truncated transcripts in dilated cardiomyopathy (DCM) undergo nonsense mediated decay (PMID: 25589632). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Protein truncating variants in this gene are known to have reduced penetrance in DCM (PMID: 25589632). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to alanine. (I) 0219 - This variant is non-coding in an alternative transcript. It is coding only in NM_133379.4, the novex-3 isoform, which is mainly expressed in sarcomeres, but also has been found in skeletal muscle (PMID: 11717165, 28510117) and it is noncoding in all other transcripts including the NM_133378.4, the predominant isoform in skeletal muscle (NCBI). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (100 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been identified in an individual with Leigh syndrome, who also harboured many other variants including the p.(Val5443Ala) in the TTN gene, however phenotype was not regarded as a match (Lake, N.J. (2018)). In addition, it has been reported as a VUS (ClinVar) and likely benign (LOVD). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not specified Benign:1
The p.Val5443Ala variant in TTN is classified as likely benign because it has been identified in 0.065% (84/128194) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It is also located in an exon that is not highly expressed in the heart and is only present in a transcript (Novex -3) whose function is unclear. ACMG/AMP Criteria applied: BP1, BS1. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at