chr1-201039955-AGTAGCTCT-A
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBS1BS2
The NM_000069.3(CACNA1S):βc.5490_5497delβ(p.Leu1832ArgfsTer67) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,614,182 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely benign (β β ).
Frequency
Genomes: π 0.0056 ( 10 hom., cov: 34)
Exomes π: 0.00055 ( 5 hom. )
Consequence
CACNA1S
NM_000069.3 frameshift
NM_000069.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.60
Genes affected
CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0235 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
BP6
Variant 1-201039955-AGTAGCTCT-A is Benign according to our data. Variant chr1-201039955-AGTAGCTCT-A is described in ClinVar as [Likely_benign]. Clinvar id is 254849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00561 (855/152314) while in subpopulation AFR AF= 0.0197 (817/41570). AF 95% confidence interval is 0.0185. There are 10 homozygotes in gnomad4. There are 398 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 10 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1S | NM_000069.3 | c.5490_5497del | p.Leu1832ArgfsTer67 | frameshift_variant | 44/44 | ENST00000362061.4 | NP_000060.2 | |
LOC101929305 | XR_922410.3 | n.1378-1897_1378-1890del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1S | ENST00000362061.4 | c.5490_5497del | p.Leu1832ArgfsTer67 | frameshift_variant | 44/44 | 1 | NM_000069.3 | ENSP00000355192 | P2 | |
ENST00000415359.1 | n.211-1897_211-1890del | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.00557 AC: 848AN: 152196Hom.: 10 Cov.: 34
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GnomAD3 exomes AF: 0.00126 AC: 316AN: 251410Hom.: 2 AF XY: 0.000949 AC XY: 129AN XY: 135878
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GnomAD4 exome AF: 0.000545 AC: 797AN: 1461868Hom.: 5 AF XY: 0.000484 AC XY: 352AN XY: 727236
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GnomAD4 genome AF: 0.00561 AC: 855AN: 152314Hom.: 10 Cov.: 34 AF XY: 0.00534 AC XY: 398AN XY: 74486
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 30, 2019 | - - |
Hypokalemic periodic paralysis, type 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Congenital myopathy 18 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Thyrotoxic periodic paralysis, susceptibility to, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Malignant hyperthermia, susceptibility to, 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at