1-201077916-G-C
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000069.3(CACNA1S):c.1582C>G(p.Arg528Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R528L) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
CACNA1S
NM_000069.3 missense
NM_000069.3 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 3.38
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 Pathogenic. Variant got 11 ACMG points.
PM1
In a transmembrane_region Helical; Name=S4 of repeat II (size 18) in uniprot entity CAC1S_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_000069.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-201077916-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 849085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968
PP5
Variant 1-201077916-G-C is Pathogenic according to our data. Variant chr1-201077916-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 21034.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-201077916-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Hypokalemic periodic paralysis, type 1 Pathogenic:1Other:1
Apr 12, 2022
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
- -
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
1.0
.;D
Vest4
MutPred
Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);
MVP
MPC
0.59
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at