rs145910245

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000069.3(CACNA1S):c.4060A>T(p.Thr1354Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,614,210 control chromosomes in the GnomAD database, including 34 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. T1354I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0050 ( 33 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: 3.14

Publications

26 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=0.009345293).

BP6

Variant 1-201051037-T-A is Benign according to our data. Variant chr1-201051037-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161208.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00335 (511/152342) while in subpopulation NFE AF = 0.00519 (353/68026). AF 95% confidence interval is 0.00474. There are 1 homozygotes in GnomAd4. There are 241 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 33 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.4060A>T	p.Thr1354Ser	missense_variant	Exon 33 of 44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 link	c.4003A>T	p.Thr1335Ser	missense_variant	Exon 32 of 43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 link	c.4060A>T	p.Thr1354Ser	missense_variant	Exon 33 of 44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.00336

AC:

511

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00519

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00264

AC:

663

AN:

251492

AF XY:

0.00260

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.00506

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.00438

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00499

AC:

7295

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00473

AC XY:

3441

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.000836

AC:

AN:

33480

American (AMR)

AF:

0.00157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00551

AC:

144

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00191

AC:

102

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00598

AC:

6653

AN:

1111990

Other (OTH)

AF:

0.00492

AC:

297

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

384

768

1151

1535

1919

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.00335

AC:

511

AN:

152342

Hom.:

Cov.:

AF XY:

0.00323

AC XY:

241

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00115

AC:

AN:

41586

American (AMR)

AF:

0.00366

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00519

AC:

353

AN:

68026

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00342

Hom.:

Bravo

AF:

0.00322

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00236

AC:

287

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00480

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1S: BS2 -

Sep 16, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32222817, 29193480, 29212769, 27153395, 27181684, 28011884, 20861472, 24784157, 24055113, 25735680, 25637381, 24195946, 26332594, 27147545) -

Oct 19, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The CACNA1S c.4060A>T (p.Thr1354Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 287/121696 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0037758 (252/66740). This frequency is about 604 times the estimated maximal expected allele frequency of a pathogenic CACNA1S variant (0.0000063), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant was initially considered pathogenic based on a publication showing segregation of the variant in an affected family, absence in 268 control chromosomes, and functional data demonstrating abnormal Ca++ flux (Pirone_2010). Based on this evidence, Lawrence_2013 listed the variant of interest as a reportable incidental finding in exome sequencing cases. However, the high frequency of this variant in the general population puts into question the true pathogenicity of the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a VUS until additional evidence becomes available. -

Jan 07, 2019

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Oct 30, 2020

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change is predicted to replace threonine with serine at codon 1354 of the CACNA1S protein (p.(Thr1354Ser)). The threonine residue is conserved to fish species, which also have a serine residue at codon 1354 (100 vertebrates, UCSC). The variant is located in the extracellular portion of an ion transporter domain. There is a small physicochemical difference between threonine and serine. The variant is present in a large population cohort at a frequency of 0.52% in the European (non-Finnish) population (rs1145910245, gnomAD v3.0). This variant has been reported in a multigenerational family of individuals who were malignant hyperthermia susceptible (PMID: 20861472) and in two unrelated individuals in an Australian cohort, one of which also had a variant in RYR1 (PMID: 25735680). Patch-clamp analyses demonstrate accelerated inward Ca2+ current and increased sensitisation of RYR1 under caffeine exposure in a transfection model. Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predicting benign/neutral effect, 2/6 algorithms predicting deleterious effect). Based on the classification guidelines RMH Modified ACMG Guidelines v1.3.0, this variant is classified as BENIGN. The following criteria are met: BA1, PP1_Moderate. -

not specified

Uncertain:1

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.4% (252/66740) Europeans. Classified as VUS in 3 papers (7 total papers in HGMD) -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

CACNA1S-related disorder

Benign:1

Feb 16, 2023

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). -

Inborn genetic diseases

Benign:1

Dec 21, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign:1

Feb 02, 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

0.098

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Uncertain

0.13

CADD

Benign

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.28

T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.83

T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.0093

T;T

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

-1.3

.;N

PhyloP100

3.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

1.6

N;N

REVEL

Uncertain

0.57

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.090

.;B

Vest4

0.28

MutPred

0.57

.;Gain of disorder (P = 0.086);

MVP

0.87

MPC

0.093

ClinPred

0.034

GERP RS

4.4

Varity_R

0.22

gMVP

0.58

Mutation Taster

=93/7

polymorphism

(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