15-33548210-G-A
Position:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001036.6(RYR3):c.815+6G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000057 in 1,403,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000057 ( 0 hom. )
Consequence
RYR3
NM_001036.6 splice_donor_region, intron
NM_001036.6 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.002170
2
Clinical Significance
Conservation
PhyloP100: 1.11
Genes affected
RYR3 (HGNC:10485): (ryanodine receptor 3) The protein encoded by this gene is a ryanodine receptor, which functions to release calcium from intracellular storage for use in many cellular processes. For example, the encoded protein is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR3 | NM_001036.6 | c.815+6G>A | splice_donor_region_variant, intron_variant | ENST00000634891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR3 | ENST00000634891.2 | c.815+6G>A | splice_donor_region_variant, intron_variant | 1 | NM_001036.6 | P4 | |||
RYR3 | ENST00000389232.9 | c.815+6G>A | splice_donor_region_variant, intron_variant | 5 | A1 | ||||
RYR3 | ENST00000415757.7 | c.815+6G>A | splice_donor_region_variant, intron_variant | 2 | A2 | ||||
RYR3 | ENST00000634418.1 | c.815+6G>A | splice_donor_region_variant, intron_variant | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.0000211 AC: 5AN: 236654Hom.: 0 AF XY: 0.0000234 AC XY: 3AN XY: 128048
GnomAD3 exomes
AF:
AC:
5
AN:
236654
Hom.:
AF XY:
AC XY:
3
AN XY:
128048
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000570 AC: 8AN: 1403528Hom.: 0 Cov.: 25 AF XY: 0.00000856 AC XY: 6AN XY: 700984
GnomAD4 exome
AF:
AC:
8
AN:
1403528
Hom.:
Cov.:
25
AF XY:
AC XY:
6
AN XY:
700984
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 577384). This variant has not been reported in the literature in individuals affected with RYR3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.03%). This sequence change falls in intron 9 of the RYR3 gene. It does not directly change the encoded amino acid sequence of the RYR3 protein. It affects a nucleotide within the consensus splice site. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at