rs3850625

chr1-201047168-G-A

Variant summary

Our verdict is Benign. Variant got -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:12

Conservation

PhyloP100: 7.71

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr1-201047168-G-A is described in Lovd as [Benign].

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/exons	MANE	UniProt
CACNA1S	NM_000069.3 linkuse as main transcript	c.4615C>T	p.Arg1539Cys	missense_variant	38/44	ENST00000362061.4
CACNA1S	XM_005245478.4 linkuse as main transcript	c.4558C>T	p.Arg1520Cys	missense_variant	37/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.4615C>T	p.Arg1539Cys	missense_variant	38/44	1	NM_000069.3	P2

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

GnomAD3 exomes

AF:

0.116

AC:

29089

AN:

251466

Hom.:

2021

AF XY:

0.125

AC XY:

16929

AN XY:

135902

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 SAS exome

AF:

0.210

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

Gnomad4 AFR exome

AF:

0.0183

Gnomad4 AMR exome

AF:

0.0955

Gnomad4 ASJ exome

AF:

0.0910

Gnomad4 EAS exome

AF:

0.0352

Gnomad4 SAS exome

AF:

0.211

Gnomad4 FIN exome

AF:

0.152

Gnomad4 NFE exome

AF:

0.119

Gnomad4 OTH exome

AF:

0.109

GnomAD4 genome

AF:

0.0905

AC:

13771

AN:

152200

Hom.:

826

Cov.:

AF XY:

0.0921

AC XY:

6851

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0214

Gnomad4 AMR

AF:

0.0806

Gnomad4 ASJ

AF:

0.0916

Gnomad4 EAS

AF:

0.0367

Gnomad4 SAS

AF:

0.193

Gnomad4 FIN

AF:

0.148

Gnomad4 NFE

AF:

0.120

Gnomad4 OTH

AF:

0.0960

Alfa

AF:

0.113

Hom.:

2784

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Malignant hyperthermia, susceptibility to, 5

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Hypokalemic periodic paralysis, type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Congenital myopathy 18

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Thyrotoxic periodic paralysis, susceptibility to, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 31, 2017

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

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

MutationTaster

Benign

5.6e-8

P;P

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

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over