chr2-178595506-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate
The NM_001267550.2(TTN):c.57847+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001267550.2 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.57847+1G>A | splice_donor_variant, intron_variant | Intron 295 of 362 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.57847+1G>A | splice_donor_variant, intron_variant | Intron 295 of 362 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 4AN: 150038Hom.: 0 Cov.: 32 FAILED QC
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000988 AC: 137AN: 1386722Hom.: 0 Cov.: 34 AF XY: 0.000101 AC XY: 69AN XY: 683722
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000267 AC: 4AN: 150038Hom.: 0 Cov.: 32 AF XY: 0.0000274 AC XY: 2AN XY: 73048
ClinVar
Submissions by phenotype
not specified Uncertain:1
The c.50143+1G>A variant in TTN has been identified in 1 individual with DCM (LMM data). It has also been identified in 0.05% (34/72786) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, the sequencing quality of this region was low. This variant occurs in the invariant region (+/- 1, 2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Splice site variants and other truncating variants in TTN are associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014), where this variant is located, and/or are located in an exon that is highly expressed in the heart (Roberts 2015). In summary, the clinical significance of the c.50143+1G>A variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate. -
Cardiomyopathy Uncertain:1
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Cardiovascular phenotype Uncertain:1
The c.30652+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 122 of the TTN gene. Coding exon 122 is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This variant (referred to as c.50143+1G>A) has been detected in an individual with dilated cardiomyopathy (DCM) who also had variants in other cardiac-related genes (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. This alteration disrupts the canonical splice site and is expected to cause aberrant splicing. However, although direct evidence is unavailable, this alteration is predicted to result in an in-frame transcript that is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the predicted splice impact is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at