rs3850625

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000069.3(CACNA1S):c.4615C>T(p.Arg1539Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,613,950 control chromosomes in the GnomAD database, including 12,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1539H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.090 ( 826 hom., cov: 33)

Exomes 𝑓: 0.12 ( 11442 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 7.71

Publications

78 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017214417).

BP6

Variant 1-201047168-G-A is Benign according to our data. Variant chr1-201047168-G-A is described in ClinVar as [Benign]. Clinvar id is 197021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.4615C>T	p.Arg1539Cys	missense_variant	Exon 38 of 44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 link	c.4558C>T	p.Arg1520Cys	missense_variant	Exon 37 of 43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 link	c.4615C>T	p.Arg1539Cys	missense_variant	Exon 38 of 44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.0905

AC:

13769

AN:

152082

Hom.:

823

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0215

Gnomad AMI

AF:

0.262

Gnomad AMR

AF:

0.0809

Gnomad ASJ

AF:

0.0916

Gnomad EAS

AF:

0.0360

Gnomad SAS

AF:

0.193

Gnomad FIN

AF:

0.148

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.120

Gnomad OTH

AF:

0.0961

GnomAD2 exomes

AF:

0.116

AC:

29089

AN:

251466

AF XY:

0.125

show subpopulations

Gnomad AFR exome

AF:

0.0205

Gnomad AMR exome

AF:

0.0958

Gnomad ASJ exome

AF:

0.0926

Gnomad EAS exome

AF:

0.0333

Gnomad FIN exome

AF:

0.152

Gnomad NFE exome

AF:

0.118

Gnomad OTH exome

AF:

0.113

GnomAD4 exome

AF:

0.119

AC:

174449

AN:

1461750

Hom.:

11442

Cov.:

AF XY:

0.123

AC XY:

89401

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.0183

AC:

614

AN:

33474

American (AMR)

AF:

0.0955

AC:

4270

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0910

AC:

2378

AN:

26134

East Asian (EAS)

AF:

0.0352

AC:

1396

AN:

39686

South Asian (SAS)

AF:

0.211

AC:

18160

AN:

86254

European-Finnish (FIN)

AF:

0.152

AC:

8127

AN:

53412

Middle Eastern (MID)

AF:

0.110

AC:

637

AN:

5766

European-Non Finnish (NFE)

AF:

0.119

AC:

132257

AN:

1111906

Other (OTH)

AF:

0.109

AC:

6610

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

9372

18745

28117

37490

46862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0905

AC:

13771

AN:

152200

Hom.:

826

Cov.:

AF XY:

0.0921

AC XY:

6851

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0214

AC:

891

AN:

41556

American (AMR)

AF:

0.0806

AC:

1233

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0916

AC:

318

AN:

3472

East Asian (EAS)

AF:

0.0367

AC:

190

AN:

5180

South Asian (SAS)

AF:

0.193

AC:

931

AN:

4816

European-Finnish (FIN)

AF:

0.148

AC:

1565

AN:

10562

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.120

AC:

8188

AN:

68004

Other (OTH)

AF:

0.0960

AC:

203

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

635

1270

1906

2541

3176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.109

Hom.:

3829

Bravo

AF:

0.0809

TwinsUK

AF:

0.125

AC:

465

ALSPAC

AF:

0.127

AC:

490

ESP6500AA

AF:

0.0218

AC:

ESP6500EA

AF:

0.124

AC:

1065

ExAC

AF:

0.117

AC:

14232

Asia WGS

AF:

0.106

AC:

370

AN:

3478

EpiCase

AF:

0.119

EpiControl

AF:

0.120

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 10, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 5

Benign:3

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypokalemic periodic paralysis, type 1

Benign:2

Jan 13, 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. -

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Aug 31, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Congenital myopathy 18

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Thyrotoxic periodic paralysis, susceptibility to, 1

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

T;D

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.0

.;M

PhyloP100

7.7

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.1

D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.023

D;D

Polyphen

0.74

.;P

Vest4

0.14

MPC

0.38

ClinPred

0.062

GERP RS

5.2

Varity_R

0.71

gMVP

0.80

Mutation Taster

=64/36

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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rs3850625

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