Variant rs56183942 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000069.3(CACNA1S):c.3822C>T(p.Ile1274=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,614,218 control chromosomes in the GnomAD database, including 1,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 141 hom., cov: 32)

Exomes 𝑓: 0.020 ( 943 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.611

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

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

BP6

Variant 1-201053248-G-A is Benign according to our data. Variant chr1-201053248-G-A is described in ClinVar as [Benign]. Clinvar id is 254831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201053248-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.611 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3 linkuse as main transcript	c.3822C>T	p.Ile1274=	synonymous_variant	31/44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4 linkuse as main transcript	c.3765C>T	p.Ile1255=	synonymous_variant	30/43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.3822C>T	p.Ile1274=	synonymous_variant	31/44	1	NM_000069.3	ENSP00000355192	P2

Frequencies

GnomAD3 genomes

AF:

0.0217

AC:

3311

AN:

152236

Hom.:

137

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0382

Gnomad ASJ

AF:

0.0233

Gnomad EAS

AF:

0.175

Gnomad SAS

AF:

0.0438

Gnomad FIN

AF:

0.00593

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0126

Gnomad OTH

AF:

0.0320

GnomAD3 exomes

AF:

0.0370

AC:

9299

AN:

251396

Hom.:

434

AF XY:

0.0353

AC XY:

4798

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0121

Gnomad AMR exome

AF:

0.0727

Gnomad ASJ exome

AF:

0.0269

Gnomad EAS exome

AF:

0.172

Gnomad SAS exome

AF:

0.0422

Gnomad FIN exome

AF:

0.00776

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.0293

GnomAD4 exome

AF:

0.0204

AC:

29863

AN:

1461864

Hom.:

943

Cov.:

AF XY:

0.0210

AC XY:

15238

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0140

Gnomad4 AMR exome

AF:

0.0705

Gnomad4 ASJ exome

AF:

0.0280

Gnomad4 EAS exome

AF:

0.171

Gnomad4 SAS exome

AF:

0.0422

Gnomad4 FIN exome

AF:

0.00779

Gnomad4 NFE exome

AF:

0.0116

Gnomad4 OTH exome

AF:

0.0256

GnomAD4 genome

AF:

0.0219

AC:

3335

AN:

152354

Hom.:

141

Cov.:

AF XY:

0.0228

AC XY:

1701

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0128

Gnomad4 AMR

AF:

0.0382

Gnomad4 ASJ

AF:

0.0233

Gnomad4 EAS

AF:

0.175

Gnomad4 SAS

AF:

0.0443

Gnomad4 FIN

AF:

0.00593

Gnomad4 NFE

AF:

0.0126

Gnomad4 OTH

AF:

0.0388

Alfa

AF:

0.0160

Hom.:

Bravo

AF:

0.0261

Asia WGS

AF:

0.108

AC:

376

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 5

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2016	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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 30, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital myopathy 18

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Thyrotoxic periodic paralysis, susceptibility to, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over