rs78835441
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP2
The NM_000540.3(RYR1):c.2004C>A(p.Asp668Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D668D) has been classified as Likely benign.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.2004C>A | p.Asp668Glu | missense_variant | 18/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.2004C>A | p.Asp668Glu | missense_variant | 18/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.2004C>A | p.Asp668Glu | missense_variant | 18/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.2004C>A | p.Asp668Glu | missense_variant, NMD_transcript_variant | 18/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251178Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135798
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461740Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727172
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 27, 2023 | Variant summary: RYR1 c.2004C>A (p.Asp668Glu) results in a conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251178 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2004C>A in individuals affected with Malignant Hyperthermia Susceptibility and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
RYR1-Related Disorders Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 02, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at