rs763695518
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000362061.4(CACNA1S):c.4795C>T(p.Arg1599Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,112 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1599Q) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000362061.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1S | NM_000069.3 | c.4795C>T | p.Arg1599Trp | missense_variant, splice_region_variant | 39/44 | ENST00000362061.4 | NP_000060.2 | |
CACNA1S | XM_005245478.4 | c.4738C>T | p.Arg1580Trp | missense_variant, splice_region_variant | 38/43 | XP_005245535.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1S | ENST00000362061.4 | c.4795C>T | p.Arg1599Trp | missense_variant, splice_region_variant | 39/44 | 1 | NM_000069.3 | ENSP00000355192 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151906Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251210Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135786
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461206Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 726914
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151906Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74158
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 08, 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 473998). This variant has not been reported in the literature in individuals affected with CACNA1S-related conditions. This variant is present in population databases (rs763695518, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1599 of the CACNA1S protein (p.Arg1599Trp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at