rs145039828
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000069.3(CACNA1S):c.3406G>A(p.Gly1136Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1136D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000069.3 missense
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 | UniProt |
---|---|---|---|---|---|---|---|
CACNA1S | NM_000069.3 | c.3406G>A | p.Gly1136Ser | missense_variant | 26/44 | ENST00000362061.4 | |
CACNA1S | XM_005245478.4 | c.3406G>A | p.Gly1136Ser | missense_variant | 26/43 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1S | ENST00000362061.4 | c.3406G>A | p.Gly1136Ser | missense_variant | 26/44 | 1 | NM_000069.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152096Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000111 AC: 28AN: 251480Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135914
GnomAD4 exome AF: 0.0000458 AC: 67AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.0000578 AC XY: 42AN XY: 727248
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152096Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74290
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 05, 2022 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2022 | The c.3406G>A (p.G1136S) alteration is located in exon 26 (coding exon 26) of the CACNA1S gene. This alteration results from a G to A substitution at nucleotide position 3406, causing the glycine (G) at amino acid position 1136 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Malignant hyperthermia, susceptibility to, 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces glycine with serine at codon 1136 of the CACNA1S protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CACNA1S-related disorders in the literature. This variant has been identified in 32/282872 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at