rs794729150
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1PP5BS2
The ENST00000369519.4(RBM20):c.2062C>T(p.Arg688Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000967 in 1,551,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000369519.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RBM20 | NM_001134363.3 | c.2062C>T | p.Arg688Ter | stop_gained | 9/14 | ENST00000369519.4 | NP_001127835.2 | |
RBM20 | XM_017016103.3 | c.1897C>T | p.Arg633Ter | stop_gained | 9/14 | XP_016871592.1 | ||
RBM20 | XM_017016104.3 | c.1678C>T | p.Arg560Ter | stop_gained | 9/14 | XP_016871593.1 | ||
RBM20 | XM_047425116.1 | c.1678C>T | p.Arg560Ter | stop_gained | 9/14 | XP_047281072.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RBM20 | ENST00000369519.4 | c.2062C>T | p.Arg688Ter | stop_gained | 9/14 | 1 | NM_001134363.3 | ENSP00000358532 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152120Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000858 AC: 12AN: 1399394Hom.: 0 Cov.: 32 AF XY: 0.0000116 AC XY: 8AN XY: 690200
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74306
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1DD Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change creates a premature translational stop signal (p.Arg688*) in the RBM20 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in RBM20 cause disease. This variant is present in population databases (rs794729150, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with clinical features of RBM20-related conditions (PMID: 25979592, 28798025, 31514951; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 202065). For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 20, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 23, 2021 | The p.R688* variant (also known as c.2062C>T), located in coding exon 9 of the RBM20 gene, results from a C to T substitution at nucleotide position 2062. This changes the amino acid from an arginine to a stop codon within coding exon 9. This variant has been detected in individuals from dilated cardiomyopathy and left ventricular noncompaction cohorts, and in cohorts referred for cardiomyopathy genetic testing; however, in most cases, clinical detail was limited or additional variants in other cardiac-related genes were also detected (Waldmüller S et al. Mol Cell Probes, 2015 Oct;29:308-14; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10; Gigli M et al. J Am Coll Cardiol, 2019 09;74:1480-1490; Parikh VN et al. Circ Heart Fail, 2019 03;12:e005371). This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of RBM20 has not been clearly established as a mechanism of disease. 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