chr1-201094018-T-C
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000069.3(CACNA1S):c.262A>G(p.Lys88Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
CACNA1S
NM_000069.3 missense
NM_000069.3 missense
Scores
2
9
8
Clinical Significance
Conservation
PhyloP100: 3.28
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 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3664622).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CACNA1S | NM_000069.3 | c.262A>G | p.Lys88Glu | missense_variant | 3/44 | ENST00000362061.4 | NP_000060.2 | |
| CACNA1S | XM_005245478.4 | c.262A>G | p.Lys88Glu | missense_variant | 3/43 | XP_005245535.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CACNA1S | ENST00000362061.4 | c.262A>G | p.Lys88Glu | missense_variant | 3/44 | 1 | NM_000069.3 | ENSP00000355192.3 |
Frequencies
GnomAD3 genomes 0.000158 AC: 24AN: 152144Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
24
AN:
152144
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000239 AC: 60AN: 251472Hom.: 0 AF XY: 0.000250 AC XY: 34AN XY: 135914
GnomAD3 exomes
AF:
AC:
60
AN:
251472
Hom.:
AF XY:
AC XY:
34
AN XY:
135914
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000153 AC: 224AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.000166 AC XY: 121AN XY: 727236
GnomAD4 exome
AF:
AC:
224
AN:
1461864
Hom.:
Cov.:
32
AF XY:
AC XY:
121
AN XY:
727236
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000158 AC: 24AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74328
GnomAD4 genome
AF:
AC:
24
AN:
152144
Hom.:
Cov.:
32
AF XY:
AC XY:
12
AN XY:
74328
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
3
ExAC
AF:
AC:
34
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 5 Uncertain:3
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CACNA1S p.Lys88Glu variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The variant was identified in ClinVar (Variant of uncertain significance; classified as uncertain significance by Invitae in 2017, EGL Genetic Diagnostics in 2017, and GeneDx in 2018), LOVD 3.0 (1 submission, likely benign) and dbSNP (rs140330831, Uncertain) databases. The variant was identified in control databases in 67 of 282844 chromosomes at a frequency of 0.0002369 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 57 of 129164 chromosomes (freq: 0.000441), Other in 2 of 7224 chromosomes (freq: 0.000277), Ashkenazi Jewish in 2 of 10370 chromosomes (freq: 0.000193), European (Finnish) in 3 of 25120 chromosomes (freq: 0.000119), Latino in 3 of 35440 chromosomes (freq: 0.000085), but was not observed in the African, East Asian, or South Asian populations. The variant was identified in 1/1740 alleles of adults unselected for malignant hyperthermia (Gonsalves_2013_PMID: 24195946). The p.Lys88 residue is conserved in mammals but not in more istantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster, DANN, MT, FATHMM, MetaLR, Revel) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 23, 2024 | This missense variant replaces lysine with glutamic acid at codon 88 of the CACNA1S protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 67/282844 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 22, 2023 | This missense variant replaces lysine with glutamic acid at codon 88 of the CACNA1S protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 67/282844 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. - |
Hypokalemic periodic paralysis, type 1 Uncertain:2
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CACNA1S p.Lys88Glu variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The variant was identified in ClinVar (Variant of uncertain significance; classified as uncertain significance by Invitae in 2017, EGL Genetic Diagnostics in 2017, and GeneDx in 2018), LOVD 3.0 (1 submission, likely benign) and dbSNP (rs140330831, Uncertain) databases. The variant was identified in control databases in 67 of 282844 chromosomes at a frequency of 0.0002369 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 57 of 129164 chromosomes (freq: 0.000441), Other in 2 of 7224 chromosomes (freq: 0.000277), Ashkenazi Jewish in 2 of 10370 chromosomes (freq: 0.000193), European (Finnish) in 3 of 25120 chromosomes (freq: 0.000119), Latino in 3 of 35440 chromosomes (freq: 0.000085), but was not observed in the African, East Asian, or South Asian populations. The variant was identified in 1/1740 alleles of adults unselected for malignant hyperthermia (Gonsalves_2013_PMID: 24195946). The p.Lys88 residue is conserved in mammals but not in more istantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster, DANN, MT, FATHMM, MetaLR, Revel) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.Disease Information: Heterozygous pathogenic variants in CACNA1S cause hypokalemic periodic paralysis type 1 (OMIM: 170400).  Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. (Verbatim, GeneReviews) Heterozygous pathogenic variants in CACNA1S are also associated with susceptibility to malignant hyperthermia (OMIM: 601887). Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances cause uncontrolled release of calcium from the sarcoplasmic reticulum and may promote entry of extracellular calcium into the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even cardiac arrest, and myoglobinuria with a risk for renal failure. (Verbatim, GeneReviews) Heterozygous pathogenic variants in CACNA1S are also associated with susceptibility to thyrotoxic periodic paralysis (OMIM: 188580). Thyrotoxic periodic paralysis is a sporadic muscle disorder characterized by episodic attacks of weakness - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Jun 28, 2022 | PM2, PP3 - |
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 29, 2024 | Reported previously in an individual who underwent exome sequencing, however clinical information was not provided and segregation analysis was not performed (PMID: 24195946); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24195946) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 06, 2017 | - - |
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 | Feb 13, 2022 | - - |
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 09, 2021 | The c.262A>G (p.K88E) alteration is located in exon 3 (coding exon 3) of the CACNA1S gene. This alteration results from a A to G substitution at nucleotide position 262, causing the lysine (K) at amino acid position 88 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Thyrotoxic periodic paralysis, susceptibility to, 1 Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CACNA1S p.Lys88Glu variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The variant was identified in ClinVar (Variant of uncertain significance; classified as uncertain significance by Invitae in 2017, EGL Genetic Diagnostics in 2017, and GeneDx in 2018), LOVD 3.0 (1 submission, likely benign) and dbSNP (rs140330831, Uncertain) databases. The variant was identified in control databases in 67 of 282844 chromosomes at a frequency of 0.0002369 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 57 of 129164 chromosomes (freq: 0.000441), Other in 2 of 7224 chromosomes (freq: 0.000277), Ashkenazi Jewish in 2 of 10370 chromosomes (freq: 0.000193), European (Finnish) in 3 of 25120 chromosomes (freq: 0.000119), Latino in 3 of 35440 chromosomes (freq: 0.000085), but was not observed in the African, East Asian, or South Asian populations. The variant was identified in 1/1740 alleles of adults unselected for malignant hyperthermia (Gonsalves_2013_PMID: 24195946). The p.Lys88 residue is conserved in mammals but not in more istantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster, DANN, MT, FATHMM, MetaLR, Revel) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.Disease Information: Heterozygous pathogenic variants in CACNA1S cause hypokalemic periodic paralysis type 1 (OMIM: 170400).  Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. (Verbatim, GeneReviews) Heterozygous pathogenic variants in CACNA1S are also associated with susceptibility to malignant hyperthermia (OMIM: 601887). Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances cause uncontrolled release of calcium from the sarcoplasmic reticulum and may promote entry of extracellular calcium into the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even cardiac arrest, and myoglobinuria with a risk for renal failure. (Verbatim, GeneReviews) Heterozygous pathogenic variants in CACNA1S are also associated with susceptibility to thyrotoxic periodic paralysis (OMIM: 188580). Thyrotoxic periodic paralysis is a sporadic muscle disorder characterized by episodic attacks of weakness - |
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 10, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;M
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
D;D
Sift4G
Benign
T;T
Polyphen
0.48
.;P
Vest4
MVP
MPC
0.39
ClinPred
T
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