1-201069522-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000069.3(CACNA1S):c.2440G>A(p.Ala814Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,592,980 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign 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. A814P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 6 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 3.32

Publications

6 publications found

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]

CACNA1S Gene-Disease associations (from GenCC):

congenital myopathy 18
Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hypokalemic periodic paralysis, type 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
malignant hyperthermia, susceptibility to, 5
Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
congenital myopathy
Inheritance: SD, AR, AD Classification: STRONG Submitted by: Illumina, Genomics England PanelApp
hypokalemic periodic paralysis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA1S links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024012804).

BP6

Variant 1-201069522-C-T is Benign according to our data. Variant chr1-201069522-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 294744.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00131 (200/152254) while in subpopulation NFE AF = 0.00237 (161/68024). AF 95% confidence interval is 0.00207. There are 0 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.2440G>A	p.Ala814Thr	missense_variant	Exon 18 of 44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 link	c.2440G>A	p.Ala814Thr	missense_variant	Exon 18 of 43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 link	c.2440G>A	p.Ala814Thr	missense_variant	Exon 18 of 44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

200

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00237

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00121

AC:

254

AN:

210546

AF XY:

0.00119

show subpopulations

Gnomad AFR exome

AF:

0.000293

Gnomad AMR exome

AF:

0.000458

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000164

Gnomad NFE exome

AF:

0.00205

Gnomad OTH exome

AF:

0.00188

GnomAD4 exome

AF:

0.00198

AC:

2846

AN:

1440726

Hom.:

Cov.:

AF XY:

0.00190

AC XY:

1357

AN XY:

714162

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33406

American (AMR)

AF:

0.000580

AC:

AN:

39678

Ashkenazi Jewish (ASJ)

AF:

0.00269

AC:

AN:

25614

East Asian (EAS)

AF:

0.0000256

AC:

AN:

38992

South Asian (SAS)

AF:

0.000219

AC:

AN:

82094

European-Finnish (FIN)

AF:

0.000134

AC:

AN:

52128

Middle Eastern (MID)

AF:

0.000699

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00236

AC:

2605

AN:

1103208

Other (OTH)

AF:

0.00184

AC:

110

AN:

59882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

155

310

465

620

775

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00131

AC:

200

AN:

152254

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41532

American (AMR)

AF:

0.000850

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00237

AC:

161

AN:

68024

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00179

Hom.:

Bravo

AF:

0.00132

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00100

AC:

120

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Jul 18, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously in an individual with susceptibility to malignant hyperthermia who also harbored another CACNA1S variant, as well as a variant in RYR1 (PMID: 25735680); Reported previously in an individual with Takotsubo (stress) cardiomyopathy and in multiple individuals participating in the deCODE Genetics project (PMID: 25132214, 37937776); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37234784, 25132214, 27153395, 25735680, 37937776) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1S: BS2 -

Malignant hyperthermia, susceptibility to, 5

Benign:2

Sep 20, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 25, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

CACNA1S-related disorder

Benign:1

Dec 08, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypokalemic periodic paralysis, type 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

D;D

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.078

MetaRNN

Benign

0.024

T;T

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

2.0

.;M

PhyloP100

3.3

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.026

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.0080

.;B

Vest4

0.36

MVP

0.90

MPC

0.10

ClinPred

0.045

GERP RS

2.7

Varity_R

0.12

gMVP

0.58

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over