rs368433841
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6
The NM_000540.3(RYR1):c.9886C>G(p.Leu3296Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L3296L) has been classified as Likely benign.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.9886C>G | p.Leu3296Val | missense_variant | 66/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.9886C>G | p.Leu3296Val | missense_variant | 66/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.9886C>G | p.Leu3296Val | missense_variant | 66/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.*629C>G | 3_prime_UTR_variant, NMD_transcript_variant | 26/49 | 1 | ||||
RYR1 | ENST00000599547.6 | c.*645C>G | 3_prime_UTR_variant, NMD_transcript_variant | 65/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000177 AC: 27AN: 152142Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000604 AC: 15AN: 248340Hom.: 0 AF XY: 0.0000372 AC XY: 5AN XY: 134548
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461590Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10AN XY: 727112
GnomAD4 genome ? AF: 0.000177 AC: 27AN: 152260Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10AN XY: 74442
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 08, 2022 | The c.9886C>G (p.L3296V) alteration is located in exon 66 (coding exon 66) of the RYR1 gene. This alteration results from a C to G substitution at nucleotide position 9886, causing the leucine (L) at amino acid position 3296 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Malignant hyperthermia, susceptibility to, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
RYR1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at