rs2296383

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000069.3(CACNA1S):c.597C>T(p.Ile199Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 1,613,646 control chromosomes in the GnomAD database, including 143,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 9766 hom., cov: 32)

Exomes 𝑓: 0.42 ( 134092 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.711

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 1-201091737-G-A is Benign according to our data. Variant chr1-201091737-G-A is described in ClinVar as Benign. ClinVar VariationId is 254852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.711 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.597C>T	p.Ile199Ile	synonymous_variant	Exon 5 of 44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 link	c.597C>T	p.Ile199Ile	synonymous_variant	Exon 5 of 43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 link	c.597C>T	p.Ile199Ile	synonymous_variant	Exon 5 of 44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.328

AC:

49894

AN:

152006

Hom.:

9768

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.436

Gnomad AMR

AF:

0.349

Gnomad ASJ

AF:

0.453

Gnomad EAS

AF:

0.366

Gnomad SAS

AF:

0.437

Gnomad FIN

AF:

0.363

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.433

Gnomad OTH

AF:

0.337

GnomAD2 exomes

AF:

0.390

AC:

97845

AN:

251092

AF XY:

0.400

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.350

Gnomad ASJ exome

AF:

0.464

Gnomad EAS exome

AF:

0.359

Gnomad FIN exome

AF:

0.366

Gnomad NFE exome

AF:

0.429

Gnomad OTH exome

AF:

0.393

GnomAD4 exome

AF:

0.424

AC:

619082

AN:

1461522

Hom.:

134092

Cov.:

AF XY:

0.426

AC XY:

309402

AN XY:

727056

show subpopulations

African (AFR)

AF:

0.0957

AC:

3205

AN:

33478

American (AMR)

AF:

0.352

AC:

15743

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.465

AC:

12159

AN:

26134

East Asian (EAS)

AF:

0.389

AC:

15438

AN:

39676

South Asian (SAS)

AF:

0.450

AC:

38841

AN:

86256

European-Finnish (FIN)

AF:

0.373

AC:

19942

AN:

53412

Middle Eastern (MID)

AF:

0.391

AC:

2256

AN:

5766

European-Non Finnish (NFE)

AF:

0.438

AC:

486611

AN:

1111706

Other (OTH)

AF:

0.412

AC:

24887

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

20025

40051

60076

80102

100127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14590

29180

43770

58360

72950

<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:

0.328

AC:

49904

AN:

152124

Hom.:

9766

Cov.:

AF XY:

0.327

AC XY:

24294

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.109

AC:

4521

AN:

41526

American (AMR)

AF:

0.349

AC:

5327

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.453

AC:

1573

AN:

3470

East Asian (EAS)

AF:

0.367

AC:

1895

AN:

5170

South Asian (SAS)

AF:

0.438

AC:

2108

AN:

4818

European-Finnish (FIN)

AF:

0.363

AC:

3842

AN:

10570

Middle Eastern (MID)

AF:

0.354

AC:

104

AN:

294

European-Non Finnish (NFE)

AF:

0.433

AC:

29421

AN:

67972

Other (OTH)

AF:

0.339

AC:

715

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1604

3209

4813

6418

8022

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

508

1016

1524

2032

2540

<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:

0.395

Hom.:

27009

Bravo

AF:

0.315

Asia WGS

AF:

0.394

AC:

1371

AN:

3478

EpiCase

AF:

0.430

EpiControl

AF:

0.425

ClinVar

Significance: Benign

Submissions summary: Benign:10

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

- -

Jul 21, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 05, 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. -

Hypokalemic periodic paralysis, type 1

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:2

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Malignant hyperthermia, susceptibility to, 5

Benign:2

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

- -

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

-0.31

CADD

Benign

6.7

(source)

DANN

Benign

0.76

PhyloP100

-0.71

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