rs4915477

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.1551T>C(p.Gly517Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 1,613,174 control chromosomes in the GnomAD database, including 337,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 37788 hom., cov: 33)

Exomes 𝑓: 0.63 ( 299855 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.15

Publications

23 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=-0.78).

BP6

Variant 1-201077947-A-G is Benign according to our data. Variant chr1-201077947-A-G is described in ClinVar as Benign. ClinVar VariationId is 254800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.15 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.1551T>C	p.Gly517Gly	synonymous_variant	Exon 11 of 44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 link	c.1551T>C	p.Gly517Gly	synonymous_variant	Exon 11 of 43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 link	c.1551T>C	p.Gly517Gly	synonymous_variant	Exon 11 of 44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.685

AC:

104086

AN:

152006

Hom.:

37747

Cov.:

show subpopulations

Gnomad AFR

AF:

0.893

Gnomad AMI

AF:

0.689

Gnomad AMR

AF:

0.652

Gnomad ASJ

AF:

0.712

Gnomad EAS

AF:

0.234

Gnomad SAS

AF:

0.295

Gnomad FIN

AF:

0.522

Gnomad MID

AF:

0.728

Gnomad NFE

AF:

0.651

Gnomad OTH

AF:

0.690

GnomAD2 exomes

AF:

0.579

AC:

145567

AN:

251274

AF XY:

0.567

show subpopulations

Gnomad AFR exome

AF:

0.896

Gnomad AMR exome

AF:

0.586

Gnomad ASJ exome

AF:

0.706

Gnomad EAS exome

AF:

0.225

Gnomad FIN exome

AF:

0.534

Gnomad NFE exome

AF:

0.654

Gnomad OTH exome

AF:

0.611

GnomAD4 exome

AF:

0.630

AC:

919893

AN:

1461050

Hom.:

299855

Cov.:

AF XY:

0.620

AC XY:

450324

AN XY:

726856

show subpopulations

African (AFR)

AF:

0.903

AC:

30232

AN:

33474

American (AMR)

AF:

0.590

AC:

26367

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.712

AC:

18608

AN:

26130

East Asian (EAS)

AF:

0.256

AC:

10171

AN:

39680

South Asian (SAS)

AF:

0.321

AC:

27662

AN:

86240

European-Finnish (FIN)

AF:

0.545

AC:

29107

AN:

53418

Middle Eastern (MID)

AF:

0.664

AC:

3831

AN:

5766

European-Non Finnish (NFE)

AF:

0.663

AC:

736271

AN:

1111270

Other (OTH)

AF:

0.624

AC:

37644

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

16585

33170

49755

66340

82925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18962

37924

56886

75848

94810

<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:

0.685

AC:

104183

AN:

152124

Hom.:

37788

Cov.:

AF XY:

0.668

AC XY:

49693

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.893

AC:

37085

AN:

41524

American (AMR)

AF:

0.651

AC:

9949

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.712

AC:

2468

AN:

3468

East Asian (EAS)

AF:

0.234

AC:

1210

AN:

5162

South Asian (SAS)

AF:

0.295

AC:

1422

AN:

4816

European-Finnish (FIN)

AF:

0.522

AC:

5529

AN:

10588

Middle Eastern (MID)

AF:

0.735

AC:

216

AN:

294

European-Non Finnish (NFE)

AF:

0.651

AC:

44222

AN:

67972

Other (OTH)

AF:

0.689

AC:

1455

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1549

3098

4648

6197

7746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

766

1532

2298

3064

3830

<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:

0.681

Hom.:

59945

Bravo

AF:

0.710

Asia WGS

AF:

0.302

AC:

1057

AN:

3478

EpiCase

AF:

0.661

EpiControl

AF:

0.677

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

not provided

Benign:3

Feb 11, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: c.1551T>C affects a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts this variant to be benign. 4/5 in silico tools via Alamut predict no change on RNA splicing site and ESEfinder predicts a gain of binding motif for splicing enhancer. This variant was found in 70806/121258 control chromosomes (with 22620 homozygotes) from ExAC at a frequency of 0.5839285, which significantly exceeds the maximal expected frequency of a pathogenic allele (0.0000013), suggesting this variant is a benign polymorphism. Taken together, considering the high frequency in controls and lack of predicted effect on splicing, this variant was classified as Benign. -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 11940049) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hypokalemic periodic paralysis, type 1

Benign:2

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Mar 28, 2019

Color Diagnostics, LLC DBA Color 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

-0.78

CADD

Benign

0.90

(source)

DANN

Benign

0.60

PhyloP100

-1.1

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