NM_000069.3:c.1373T>A

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.1373T>A(p.Leu458His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,613,504 control chromosomes in the GnomAD database, including 94,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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 Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L458L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.24 ( 5762 hom., cov: 33)

Exomes 𝑓: 0.33 ( 88432 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.19

Publications

33 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=0.004697144).

BP6

Variant 1-201083182-A-T is Benign according to our data. Variant chr1-201083182-A-T is described in ClinVar as Benign. ClinVar VariationId is 254789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.1373T>A	p.Leu458His	missense_variant	Exon 10 of 44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 link	c.1373T>A	p.Leu458His	missense_variant	Exon 10 of 43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 link	c.1373T>A	p.Leu458His	missense_variant	Exon 10 of 44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

36303

AN:

151934

Hom.:

5759

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0729

Gnomad AMI

AF:

0.345

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.307

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.133

Gnomad FIN

AF:

0.207

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.368

Gnomad OTH

AF:

0.236

GnomAD2 exomes

AF:

0.239

AC:

60095

AN:

251056

AF XY:

0.245

show subpopulations

Gnomad AFR exome

AF:

0.0648

Gnomad AMR exome

AF:

0.139

Gnomad ASJ exome

AF:

0.299

Gnomad EAS exome

AF:

0.000491

Gnomad FIN exome

AF:

0.205

Gnomad NFE exome

AF:

0.359

Gnomad OTH exome

AF:

0.273

GnomAD4 exome

AF:

0.331

AC:

483449

AN:

1461452

Hom.:

88432

Cov.:

AF XY:

0.326

AC XY:

236918

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.0600

AC:

2010

AN:

33478

American (AMR)

AF:

0.147

AC:

6589

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.302

AC:

7895

AN:

26132

East Asian (EAS)

AF:

0.000781

AC:

AN:

39670

South Asian (SAS)

AF:

0.142

AC:

12285

AN:

86250

European-Finnish (FIN)

AF:

0.217

AC:

11599

AN:

53400

Middle Eastern (MID)

AF:

0.213

AC:

1225

AN:

5764

European-Non Finnish (NFE)

AF:

0.381

AC:

423900

AN:

1111664

Other (OTH)

AF:

0.297

AC:

17915

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

16857

33714

50572

67429

84286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12890

25780

38670

51560

64450

<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:

0.239

AC:

36307

AN:

152052

Hom.:

5762

Cov.:

AF XY:

0.227

AC XY:

16912

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0729

AC:

3029

AN:

41546

American (AMR)

AF:

0.231

AC:

3528

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

1065

AN:

3464

East Asian (EAS)

AF:

0.000965

AC:

AN:

5182

South Asian (SAS)

AF:

0.134

AC:

646

AN:

4822

European-Finnish (FIN)

AF:

0.207

AC:

2184

AN:

10576

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.368

AC:

24987

AN:

67876

Other (OTH)

AF:

0.233

AC:

491

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1354

2708

4062

5416

6770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

366

732

1098

1464

1830

<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:

0.334

Hom.:

6894

Bravo

AF:

0.233

TwinsUK

AF:

0.383

AC:

1419

ALSPAC

AF:

0.369

AC:

1423

ESP6500AA

AF:

0.0765

AC:

337

ESP6500EA

AF:

0.376

AC:

3235

ExAC

AF:

0.243

AC:

29529

Asia WGS

AF:

0.0820

AC:

289

AN:

3478

EpiCase

AF:

0.353

EpiControl

AF:

0.357

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 05, 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. -

Jun 22, 2021

Athena Diagnostics

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. -

Jul 14, 2021

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

- -

Malignant hyperthermia, susceptibility to, 5

Benign:1

Feb 05, 2024

All of Us Research Program, National Institutes of Health

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

0.13

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.32

T;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.36

T;T

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;L

PhyloP100

3.2

PrimateAI

Benign

0.38

PROVEAN

Benign

1.7

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.22

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.83

.;P

Vest4

0.15

MPC

0.21

ClinPred

0.062

GERP RS

3.4

Varity_R

0.21

gMVP

0.39

Mutation Taster

=100/0

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