NM_000069.3:c.5399T>C

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.5399T>C(p.Leu1800Ser) variant causes a missense change. The variant allele was found at a frequency of 0.146 in 1,614,082 control chromosomes in the GnomAD database, including 24,387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1800L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.24 ( 7242 hom., cov: 34)

Exomes 𝑓: 0.14 ( 17145 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.82

Publications

40 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:

ENSG00000234132 (HGNC:):

ENSG00000234132 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=0.0020485818).

BP6

Variant 1-201040054-A-G is Benign according to our data. Variant chr1-201040054-A-G is described in ClinVar as Benign. ClinVar VariationId is 254847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.5399T>C	p.Leu1800Ser	missense_variant	Exon 44 of 44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 link	c.5342T>C	p.Leu1781Ser	missense_variant	Exon 43 of 43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 link	c.5399T>C	p.Leu1800Ser	missense_variant	Exon 44 of 44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.244

AC:

37109

AN:

152104

Hom.:

7235

Cov.:

show subpopulations

Gnomad AFR

AF:

0.543

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.155

Gnomad ASJ

AF:

0.156

Gnomad EAS

AF:

0.120

Gnomad SAS

AF:

0.0697

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.197

GnomAD2 exomes

AF:

0.147

AC:

36827

AN:

250696

AF XY:

0.138

show subpopulations

Gnomad AFR exome

AF:

0.560

Gnomad AMR exome

AF:

0.0878

Gnomad ASJ exome

AF:

0.158

Gnomad EAS exome

AF:

0.125

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.149

GnomAD4 exome

AF:

0.136

AC:

199110

AN:

1461860

Hom.:

17145

Cov.:

AF XY:

0.133

AC XY:

96807

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.559

AC:

18702

AN:

33480

American (AMR)

AF:

0.0948

AC:

4239

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.156

AC:

4090

AN:

26136

East Asian (EAS)

AF:

0.120

AC:

4746

AN:

39688

South Asian (SAS)

AF:

0.0729

AC:

6285

AN:

86258

European-Finnish (FIN)

AF:

0.139

AC:

7408

AN:

53408

Middle Eastern (MID)

AF:

0.123

AC:

708

AN:

5768

European-Non Finnish (NFE)

AF:

0.129

AC:

143523

AN:

1112002

Other (OTH)

AF:

0.156

AC:

9409

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

10411

20822

31234

41645

52056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5300

10600

15900

21200

26500

<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:

0.244

AC:

37143

AN:

152222

Hom.:

7242

Cov.:

AF XY:

0.238

AC XY:

17750

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.543

AC:

22527

AN:

41500

American (AMR)

AF:

0.154

AC:

2363

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.156

AC:

542

AN:

3470

East Asian (EAS)

AF:

0.120

AC:

622

AN:

5176

South Asian (SAS)

AF:

0.0690

AC:

333

AN:

4828

European-Finnish (FIN)

AF:

0.146

AC:

1550

AN:

10616

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.128

AC:

8739

AN:

68010

Other (OTH)

AF:

0.194

AC:

411

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1188

2376

3565

4753

5941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

338

676

1014

1352

1690

<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:

0.163

Hom.:

8345

Bravo

AF:

0.261

TwinsUK

AF:

0.132

AC:

489

ALSPAC

AF:

0.129

AC:

498

ESP6500AA

AF:

0.541

AC:

2385

ESP6500EA

AF:

0.131

AC:

1124

ExAC

AF:

0.155

AC:

18788

Asia WGS

AF:

0.118

AC:

409

AN:

3478

EpiCase

AF:

0.122

EpiControl

AF:

0.126

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 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. -

Jul 21, 2017

Athena Diagnostics

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

- -

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Pathogenic

0.59

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

T;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.1

.;M

PhyloP100

3.8

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.20

Sift

Uncertain

0.0010

D;D

Sift4G

Benign

0.076

T;T

Polyphen

1.0

.;D

Vest4

0.11

MPC

0.62

ClinPred

0.027

GERP RS

4.9

Varity_R

0.15

gMVP

0.56

Mutation Taster

=95/5

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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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