rs1325309

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000069.3(CACNA1S):c.153-61A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 1,421,418 control chromosomes in the GnomAD database, including 144,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 17525 hom., cov: 33)

Exomes 𝑓: 0.44 ( 127380 hom. )

Consequence

CACNA1S
NM_000069.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.916

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 1-201110330-T-A is Benign according to our data. Variant chr1-201110330-T-A is described in ClinVar as Benign. ClinVar VariationId is 678214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.794 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.153-61A>T		intron_variant	Intron 1 of 43	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 link	c.153-61A>T		intron_variant	Intron 1 of 42		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 link	c.153-61A>T		intron_variant	Intron 1 of 43	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.471

AC:

71609

AN:

151986

Hom.:

17499

Cov.:

show subpopulations

Gnomad AFR

AF:

0.544

Gnomad AMI

AF:

0.422

Gnomad AMR

AF:

0.523

Gnomad ASJ

AF:

0.408

Gnomad EAS

AF:

0.814

Gnomad SAS

AF:

0.551

Gnomad FIN

AF:

0.361

Gnomad MID

AF:

0.494

Gnomad NFE

AF:

0.404

Gnomad OTH

AF:

0.490

GnomAD4 exome

AF:

0.442

AC:

561395

AN:

1269314

Hom.:

127380

AF XY:

0.444

AC XY:

284369

AN XY:

640632

show subpopulations

African (AFR)

AF:

0.554

AC:

16623

AN:

30030

American (AMR)

AF:

0.577

AC:

25338

AN:

43938

Ashkenazi Jewish (ASJ)

AF:

0.414

AC:

10305

AN:

24916

East Asian (EAS)

AF:

0.822

AC:

31963

AN:

38880

South Asian (SAS)

AF:

0.543

AC:

44786

AN:

82510

European-Finnish (FIN)

AF:

0.379

AC:

20047

AN:

52868

Middle Eastern (MID)

AF:

0.490

AC:

2664

AN:

5440

European-Non Finnish (NFE)

AF:

0.411

AC:

384882

AN:

936702

Other (OTH)

AF:

0.459

AC:

24787

AN:

54030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

16855

33710

50566

67421

84276

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11518

23036

34554

46072

57590

<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:

0.471

AC:

71686

AN:

152104

Hom.:

17525

Cov.:

AF XY:

0.473

AC XY:

35159

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.544

AC:

22599

AN:

41514

American (AMR)

AF:

0.523

AC:

8001

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.408

AC:

1415

AN:

3466

East Asian (EAS)

AF:

0.814

AC:

4210

AN:

5170

South Asian (SAS)

AF:

0.550

AC:

2649

AN:

4820

European-Finnish (FIN)

AF:

0.361

AC:

3818

AN:

10580

Middle Eastern (MID)

AF:

0.490

AC:

144

AN:

294

European-Non Finnish (NFE)

AF:

0.404

AC:

27432

AN:

67958

Other (OTH)

AF:

0.491

AC:

1034

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1943

3885

5828

7770

9713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.444

Hom.:

1902

Bravo

AF:

0.490

Asia WGS

AF:

0.659

AC:

2288

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 18, 2018

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hypokalemic periodic paralysis, type 1

Benign:1

Jul 14, 2021

Genome-Nilou Lab

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

-0.90

CADD

Benign

1.5

(source)

DANN

Benign

0.71

PhyloP100

-0.92

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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