rs41267497

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.4860C>T(p.Pro1620Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,613,800 control chromosomes in the GnomAD database, including 18,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1166 hom., cov: 31)

Exomes 𝑓: 0.14 ( 17216 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -1.20

Publications

11 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=-0.87).

BP6

Variant 1-201043469-G-A is Benign according to our data. Variant chr1-201043469-G-A is described in ClinVar as Benign. ClinVar VariationId is 254841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.2 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.4860C>T	p.Pro1620Pro	synonymous_variant	Exon 40 of 44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 link	c.4803C>T	p.Pro1601Pro	synonymous_variant	Exon 39 of 43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 link	c.4860C>T	p.Pro1620Pro	synonymous_variant	Exon 40 of 44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15883

AN:

151930

Hom.:

1167

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0296

Gnomad AMI

AF:

0.238

Gnomad AMR

AF:

0.0901

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0218

Gnomad FIN

AF:

0.125

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.162

Gnomad OTH

AF:

0.110

GnomAD2 exomes

AF:

0.105

AC:

26402

AN:

251320

AF XY:

0.105

show subpopulations

Gnomad AFR exome

AF:

0.0262

Gnomad AMR exome

AF:

0.0672

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.161

Gnomad OTH exome

AF:

0.114

GnomAD4 exome

AF:

0.144

AC:

210454

AN:

1461752

Hom.:

17216

Cov.:

AF XY:

0.140

AC XY:

102151

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.0234

AC:

785

AN:

33478

American (AMR)

AF:

0.0697

AC:

3117

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.107

AC:

2797

AN:

26132

East Asian (EAS)

AF:

0.000277

AC:

AN:

39680

South Asian (SAS)

AF:

0.0267

AC:

2299

AN:

86236

European-Finnish (FIN)

AF:

0.131

AC:

6979

AN:

53418

Middle Eastern (MID)

AF:

0.0765

AC:

441

AN:

5768

European-Non Finnish (NFE)

AF:

0.168

AC:

186751

AN:

1111924

Other (OTH)

AF:

0.120

AC:

7274

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

10610

21220

31829

42439

53049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6490

12980

19470

25960

32450

<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:

0.104

AC:

15880

AN:

152048

Hom.:

1166

Cov.:

AF XY:

0.101

AC XY:

7472

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.0296

AC:

1229

AN:

41480

American (AMR)

AF:

0.0899

AC:

1374

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

366

AN:

3470

East Asian (EAS)

AF:

0.000388

AC:

AN:

5158

South Asian (SAS)

AF:

0.0220

AC:

106

AN:

4820

European-Finnish (FIN)

AF:

0.125

AC:

1324

AN:

10558

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.162

AC:

11004

AN:

67966

Other (OTH)

AF:

0.109

AC:

230

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

685

1370

2056

2741

3426

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<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:

0.128

Hom.:

869

Bravo

AF:

0.101

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.153

EpiControl

AF:

0.161

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 28, 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. -

Malignant hyperthermia, susceptibility to, 5

Benign:3

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

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 12, 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

-0.87

CADD

Benign

0.17

(source)

DANN

Benign

0.40

PhyloP100

-1.2

Mutation Taster

=100/0

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

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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