rs12742170

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000069.3(CACNA1S):c.1371T>G(p.Pro457Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,613,478 control chromosomes in the GnomAD database, including 94,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P457P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.24 ( 5763 hom., cov: 33)

Exomes 𝑓: 0.33 ( 88423 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.06

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 1-201083184-A-C is Benign according to our data. Variant chr1-201083184-A-C is described in ClinVar as [Benign]. Clinvar id is 254788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201083184-A-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.06 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.364 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.1371T>G	p.Pro457Pro	synonymous_variant	10/44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 linkuse as main transcript	c.1371T>G	p.Pro457Pro	synonymous_variant	10/43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.1371T>G	p.Pro457Pro	synonymous_variant	10/44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

36305

AN:

151928

Hom.:

5760

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0729

Gnomad AMI

AF:

0.345

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.133

Gnomad FIN

AF:

0.207

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.368

Gnomad OTH

AF:

0.236

GnomAD3 exomes

AF:

0.239

AC:

60097

AN:

251058

Hom.:

9155

AF XY:

0.245

AC XY:

33189

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.0648

Gnomad AMR exome

AF:

0.139

Gnomad ASJ exome

AF:

0.299

Gnomad EAS exome

AF:

0.000545

Gnomad SAS exome

AF:

0.144

Gnomad FIN exome

AF:

0.205

Gnomad NFE exome

AF:

0.359

Gnomad OTH exome

AF:

0.273

GnomAD4 exome

AF:

0.331

AC:

483427

AN:

1461434

Hom.:

88423

Cov.:

AF XY:

0.326

AC XY:

236910

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.0600

Gnomad4 AMR exome

AF:

0.147

Gnomad4 ASJ exome

AF:

0.302

Gnomad4 EAS exome

AF:

0.000781

Gnomad4 SAS exome

AF:

0.142

Gnomad4 FIN exome

AF:

0.217

Gnomad4 NFE exome

AF:

0.381

Gnomad4 OTH exome

AF:

0.297

GnomAD4 genome

AF:

0.239

AC:

36309

AN:

152044

Hom.:

5763

Cov.:

AF XY:

0.227

AC XY:

16913

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0729

Gnomad4 AMR

AF:

0.231

Gnomad4 ASJ

AF:

0.308

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.134

Gnomad4 FIN

AF:

0.207

Gnomad4 NFE

AF:

0.368

Gnomad4 OTH

AF:

0.234

Alfa

AF:

0.289

Hom.:

3249

Bravo

AF:

0.233

Asia WGS

AF:

0.0820

AC:

289

AN:

3478

EpiCase

AF:

0.353

EpiControl

AF:

0.357

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hypokalemic periodic paralysis, type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

- -

Malignant hyperthermia, susceptibility to, 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.1

DANN

Benign

0.66

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

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