1-201078005-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting

The NM_000069.3(CACNA1S):​c.1493G>A​(p.Arg498His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,614,168 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 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. R498C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

13
4
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 7.88
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.918
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000291 (425/1461836) while in subpopulation MID AF= 0.00208 (12/5768). AF 95% confidence interval is 0.0012. There are 1 homozygotes in gnomad4_exome. There are 208 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1SNM_000069.3 linkc.1493G>A p.Arg498His missense_variant Exon 11 of 44 ENST00000362061.4 NP_000060.2 Q13698
CACNA1SXM_005245478.4 linkc.1493G>A p.Arg498His missense_variant Exon 11 of 43 XP_005245535.1 B1ALM3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1SENST00000362061.4 linkc.1493G>A p.Arg498His missense_variant Exon 11 of 44 1 NM_000069.3 ENSP00000355192.3 Q13698

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152214
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000309
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000187
AC:
47
AN:
251488
Hom.:
0
AF XY:
0.000228
AC XY:
31
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000299
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000291
AC:
425
AN:
1461836
Hom.:
1
Cov.:
35
AF XY:
0.000286
AC XY:
208
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000338
Gnomad4 OTH exome
AF:
0.000397
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152332
Hom.:
0
Cov.:
31
AF XY:
0.000175
AC XY:
13
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000309
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000170
Hom.:
0
Bravo
AF:
0.000208
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000778
AC:
3
ExAC
AF:
0.000239
AC:
29
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000654
EpiControl
AF:
0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitterclinical testingAthena DiagnosticsDec 02, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024CACNA1S: PM2:Supporting -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 07, 2024Reported in an individual with exertional heat illness who harbored an additional variant in the CACNA1S gene and was not susceptible to malignant hyperthermia by in vitro contracture test (PMID: 25658027); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37937776, 32054689, 25658027, 24195946, 36796140, 36292632) -
Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1;C5830283:Congenital myopathy 18 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 28, 2024- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 14, 2023The c.1493G>A (p.R498H) alteration is located in exon 11 (coding exon 11) of the CACNA1S gene. This alteration results from a G to A substitution at nucleotide position 1493, causing the arginine (R) at amino acid position 498 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Hypokalemic periodic paralysis, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2024This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 498 of the CACNA1S protein (p.Arg498His). This variant is present in population databases (rs150590855, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of CACNA1S-related conditions (PMID: 25658027, 32054689). ClinVar contains an entry for this variant (Variation ID: 424926). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1S protein function with a positive predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.50
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.82
D;D
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.92
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.5
.;M
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-4.7
D;D
REVEL
Pathogenic
0.93
Sift
Uncertain
0.0010
D;D
Sift4G
Benign
0.072
T;T
Polyphen
1.0
.;D
Vest4
0.82
MVP
0.97
MPC
0.59
ClinPred
0.56
D
GERP RS
4.8
Varity_R
0.94
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs150590855; hg19: chr1-201047133; COSMIC: COSV62937476; API