rs12742170

chr1-201083184-A-Cchr1-201083184-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000069.3(CACNA1S):c.1371T>G(p.Pro457=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.06

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]

ACMG classification

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	UniProt
CACNA1S	NM_000069.3	c.1371T>G	p.Pro457=	synonymous_variant	10/44	ENST00000362061.4
CACNA1S	XM_005245478.4	c.1371T>G	p.Pro457=	synonymous_variant	10/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4	c.1371T>G	p.Pro457=	synonymous_variant	10/44	1	NM_000069.3	P2

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36305 AN: 151928 Hom.: 5760 Cov.: 33

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

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.: 46 AF XY: 0.326 AC XY: 236910 AN XY: 727026

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.: 33 AF XY: 0.227 AC XY: 16913 AN XY: 74346

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -

Hypokalemic periodic paralysis, type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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. -

Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	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

Other links and lift over

dbSNP: rs12742170; hg19: chr1-201052312; COSMIC: COSV62938931;