rs16847674

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000069.3(CACNA1S):c.1491C>T(p.Asn497Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.0656 in 1,614,036 control chromosomes in the GnomAD database, including 4,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.095 ( 902 hom., cov: 31)

Exomes 𝑓: 0.063 ( 3867 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.27

Publications

12 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 1-201078007-G-A is Benign according to our data. Variant chr1-201078007-G-A is described in ClinVar as Benign. ClinVar VariationId is 254795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.1491C>T	p.Asn497Asn	synonymous_variant	Exon 11 of 44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4 link	c.1491C>T	p.Asn497Asn	synonymous_variant	Exon 11 of 43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 link	c.1491C>T	p.Asn497Asn	synonymous_variant	Exon 11 of 44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes

AF:

0.0951

AC:

14472

AN:

152156

Hom.:

897

Cov.:

show subpopulations

Gnomad AFR

AF:

0.160

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.0864

Gnomad EAS

AF:

0.192

Gnomad SAS

AF:

0.0563

Gnomad FIN

AF:

0.0967

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.0502

Gnomad OTH

AF:

0.0883

GnomAD2 exomes

AF:

0.0872

AC:

21936

AN:

251492

AF XY:

0.0819

show subpopulations

Gnomad AFR exome

AF:

0.158

Gnomad AMR exome

AF:

0.133

Gnomad ASJ exome

AF:

0.0865

Gnomad EAS exome

AF:

0.183

Gnomad FIN exome

AF:

0.0965

Gnomad NFE exome

AF:

0.0538

Gnomad OTH exome

AF:

0.0721

GnomAD4 exome

AF:

0.0625

AC:

91377

AN:

1461762

Hom.:

3867

Cov.:

AF XY:

0.0621

AC XY:

45127

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.166

AC:

5545

AN:

33476

American (AMR)

AF:

0.131

AC:

5837

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0893

AC:

2333

AN:

26126

East Asian (EAS)

AF:

0.219

AC:

8686

AN:

39698

South Asian (SAS)

AF:

0.0607

AC:

5235

AN:

86254

European-Finnish (FIN)

AF:

0.0918

AC:

4903

AN:

53420

Middle Eastern (MID)

AF:

0.128

AC:

741

AN:

5768

European-Non Finnish (NFE)

AF:

0.0483

AC:

53760

AN:

1111904

Other (OTH)

AF:

0.0718

AC:

4337

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

4959

9918

14878

19837

24796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2208

4416

6624

8832

11040

<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:

0.0953

AC:

14511

AN:

152274

Hom.:

902

Cov.:

AF XY:

0.0977

AC XY:

7274

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.160

AC:

6637

AN:

41550

American (AMR)

AF:

0.103

AC:

1576

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0864

AC:

300

AN:

3472

East Asian (EAS)

AF:

0.192

AC:

991

AN:

5166

South Asian (SAS)

AF:

0.0563

AC:

272

AN:

4828

European-Finnish (FIN)

AF:

0.0967

AC:

1026

AN:

10614

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0502

AC:

3412

AN:

68016

Other (OTH)

AF:

0.0936

AC:

198

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

661

1323

1984

2646

3307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.0797

Hom.:

479

Bravo

AF:

0.101

Asia WGS

AF:

0.123

AC:

427

AN:

3478

EpiCase

AF:

0.0574

EpiControl

AF:

0.0559

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

- -

Feb 23, 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 25, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 5

Benign:3

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2019

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

BayesDel_noAF

Benign

-0.42

CADD

Benign

9.7

(source)

DANN

Benign

0.77

PhyloP100

4.3

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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