chr1-201077934-G-A

Variant names:

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.1564C>T(p.Leu522Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.215 in 1,613,632 control chromosomes in the GnomAD database, including 39,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4049 hom., cov: 33)

Exomes 𝑓: 0.21 ( 35189 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.91

Publications

18 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=-0.45).

BP6

Variant 1-201077934-G-A is Benign according to our data. Variant chr1-201077934-G-A is described in ClinVar as Benign. ClinVar VariationId is 254801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.1564C>T	p.Leu522Leu	synonymous_variant	Exon 11 of 44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4 link	c.1564C>T	p.Leu522Leu	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.1564C>T	p.Leu522Leu	synonymous_variant	Exon 11 of 44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes

AF:

0.225

AC:

34218

AN:

152086

Hom.:

4045

Cov.:

show subpopulations

Gnomad AFR

AF:

0.259

Gnomad AMI

AF:

0.285

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.221

Gnomad EAS

AF:

0.0402

Gnomad SAS

AF:

0.101

Gnomad FIN

AF:

0.217

Gnomad MID

AF:

0.283

Gnomad NFE

AF:

0.221

Gnomad OTH

AF:

0.263

GnomAD2 exomes

AF:

0.209

AC:

52602

AN:

251284

AF XY:

0.205

show subpopulations

Gnomad AFR exome

AF:

0.259

Gnomad AMR exome

AF:

0.275

Gnomad ASJ exome

AF:

0.229

Gnomad EAS exome

AF:

0.0403

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.229

Gnomad OTH exome

AF:

0.223

GnomAD4 exome

AF:

0.214

AC:

313111

AN:

1461428

Hom.:

35189

Cov.:

AF XY:

0.211

AC XY:

153600

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.255

AC:

8548

AN:

33470

American (AMR)

AF:

0.270

AC:

12063

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.229

AC:

5985

AN:

26132

East Asian (EAS)

AF:

0.0363

AC:

1440

AN:

39688

South Asian (SAS)

AF:

0.113

AC:

9717

AN:

86250

European-Finnish (FIN)

AF:

0.236

AC:

12630

AN:

53420

Middle Eastern (MID)

AF:

0.243

AC:

1404

AN:

5766

European-Non Finnish (NFE)

AF:

0.224

AC:

248763

AN:

1111608

Other (OTH)

AF:

0.208

AC:

12561

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

13259

26518

39776

53035

66294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8482

16964

25446

33928

42410

<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:

0.225

AC:

34246

AN:

152204

Hom.:

4049

Cov.:

AF XY:

0.221

AC XY:

16476

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.259

AC:

10770

AN:

41516

American (AMR)

AF:

0.248

AC:

3798

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.221

AC:

768

AN:

3470

East Asian (EAS)

AF:

0.0403

AC:

209

AN:

5192

South Asian (SAS)

AF:

0.0998

AC:

481

AN:

4820

European-Finnish (FIN)

AF:

0.217

AC:

2304

AN:

10602

Middle Eastern (MID)

AF:

0.284

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.221

AC:

15025

AN:

67994

Other (OTH)

AF:

0.260

AC:

549

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1376

2751

4127

5502

6878

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

338

676

1014

1352

1690

<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:

0.195

Hom.:

1236

Bravo

AF:

0.232

Asia WGS

AF:

0.0740

AC:

258

AN:

3478

EpiCase

AF:

0.238

EpiControl

AF:

0.247

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 21, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 5

Benign:2

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

- -

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

-0.45

CADD

Benign

8.7

(source)

DANN

Benign

0.75

PhyloP100

4.9

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