rs12742170

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000069.3(CACNA1S):c.1371T>G(p.Pro457Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,613,478 control chromosomes in the GnomAD database, including 94,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P457P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.24 ( 5763 hom., cov: 33)

Exomes 𝑓: 0.33 ( 88423 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.06

Publications

13 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 1-201083184-A-C is Benign according to our data. Variant chr1-201083184-A-C is described in ClinVar as Benign. ClinVar VariationId is 254788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.06 with no splicing effect.

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.1371T>G	p.Pro457Pro	synonymous_variant	Exon 10 of 44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 link	c.1371T>G	p.Pro457Pro	synonymous_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.1371T>G	p.Pro457Pro	synonymous_variant	Exon 10 of 44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

36305

AN:

151928

Hom.:

5760

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0729

Gnomad AMI

AF:

0.345

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.308

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:

60097

AN:

251058

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:

0.000545

Gnomad FIN exome

AF:

0.205

Gnomad NFE exome

AF:

0.359

Gnomad OTH exome

AF:

0.273

GnomAD4 exome

AF:

0.331

AC:

483427

AN:

1461434

Hom.:

88423

Cov.:

AF XY:

0.326

AC XY:

236910

AN XY:

727026

show subpopulations

African (AFR)

AF:

0.0600

AC:

2010

AN:

33478

American (AMR)

AF:

0.147

AC:

6588

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.302

AC:

7893

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:

11601

AN:

53402

Middle Eastern (MID)

AF:

0.213

AC:

1225

AN:

5758

European-Non Finnish (NFE)

AF:

0.381

AC:

423878

AN:

1111646

Other (OTH)

AF:

0.297

AC:

17916

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

16817

33634

50452

67269

84086

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12888

25776

38664

51552

64440

<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:

36309

AN:

152044

Hom.:

5763

Cov.:

AF XY:

0.227

AC XY:

16913

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0729

AC:

3029

AN:

41542

American (AMR)

AF:

0.231

AC:

3529

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

1065

AN:

3460

East Asian (EAS)

AF:

0.000966

AC:

AN:

5178

South Asian (SAS)

AF:

0.134

AC:

646

AN:

4820

European-Finnish (FIN)

AF:

0.207

AC:

2184

AN:

10576

Middle Eastern (MID)

AF:

0.202

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.368

AC:

24988

AN:

67888

Other (OTH)

AF:

0.234

AC:

491

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1366

2731

4097

5462

6828

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:

0.274

Hom.:

3986

Bravo

AF:

0.233

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

Jun 22, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hypokalemic periodic paralysis, type 1

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

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

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.1

(source)

DANN

Benign

0.66

PhyloP100

-3.1

Mutation Taster

=99/1

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