NM_031229.4:c.1054C>T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_031229.4(RBCK1):c.1054C>T(p.Arg352*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000161 in 1,613,952 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_031229.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RBCK1 | NM_031229.4 | c.1054C>T | p.Arg352* | stop_gained | Exon 9 of 12 | ENST00000356286.10 | NP_112506.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251356Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135862
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461834Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727226
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74300
ClinVar
Submissions by phenotype
Polyglucosan body myopathy type 1 Pathogenic:2
The c.1054C>T, p.Arg352* variant in the RBCK1 gene is a homozygous nonsense variant which results in premature truncation of the protein at exon 9/12. The allele frequency of this variant in the gnomAD database is 0.00001194 (3/251,356) without homozygotes, suggesting that it is not a common benign polymorphism in the populations presented in this database. This variant in the homozygous state has been previously reported as disease causing in one family (PMID: 23798481). Pathogenic variants in the RBCK1 gene are causative of autosomal recessive polyglucosan body myopathy 1 with or without immunodeficiency (OMIM#: 615895). Several truncating RBCK1 variants have been reported in multiple patients/families with the disease, suggesting the disease mechanism is loss of function (PMID: 23798481). -
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 580166). This premature translational stop signal has been observed in individual(s) with polyglucosan body myopathy and dilated cardiomyopathy (PMID: 23798481). This variant is present in population databases (rs780854072, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg352*) in the RBCK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RBCK1 are known to be pathogenic (PMID: 2379848, 23104095, 23889995). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at