1-201365610-A-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP5_Moderate
The NM_001276345.2(TNNT2):c.294T>A(p.Asp98Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.
Frequency
Consequence
NM_001276345.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNT2 | NM_001276345.2 | c.294T>A | p.Asp98Glu | missense_variant, splice_region_variant | 9/17 | ENST00000656932.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNT2 | ENST00000656932.1 | c.294T>A | p.Asp98Glu | missense_variant, splice_region_variant | 9/17 | NM_001276345.2 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 14, 2019 | The p.Asp88Glu (c.264T>A) variant in TNNT2 has been identified as a de novo change in 1 individual with infantile-onset DCM (LMM data), but was absent from large population studies. Additionally, a different variant resulting in the same amino acid change, c.264T>G, has been identified as a de novo change in another individual with infantile-onset DCM (LMM data). Computational prediction tools and conservation analysis suggest that the p.Asp88Glu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, this variant is located in the last three bases of the exon, which is part of the 5’ splice region. While computational tools do not predict an impact on splicing, these tools may not accurately predict biological function. In summary, although additional studies are required to fully establish its clinical significance, the p.Asp88Glu (c.264T>A) variant meets criteria to be classified as likely pathogenic for autosomal dominant dilated cardiomyopathy. ACMG/AMP Criteria applied: PM2, PM6, PP3, PS1_Supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at