rs9427714

chr1-201077983-A-G

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.1515T>C(p.Cys505=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,613,586 control chromosomes in the GnomAD database, including 94,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5892 hom., cov: 32)
  • Exomes 𝑓: 0.33 (88880 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.211

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=-0.51).
• BP6: Variant 1-201077983-A-G is Benign according to our data. Variant chr1-201077983-A-G is described in ClinVar as [Benign]. Clinvar id is 254797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201077983-A-G is described in Lovd as [Benign]. Variant chr1-201077983-A-G is described in Lovd as [Pathogenic].
• BP7: Synonymous conserved (PhyloP=0.211 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1S	NM_000069.3	c.1515T>C	p.Cys505=	synonymous_variant	11/44	ENST00000362061.4
CACNA1S	XM_005245478.4	c.1515T>C	p.Cys505=	synonymous_variant	11/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4	c.1515T>C	p.Cys505=	synonymous_variant	11/44	1	NM_000069.3	P2

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36618 AN: 152168 Hom.: 5887 Cov.: 32

Gnomad AFR AF: 0.0749

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.000960

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.234

GnomAD3 exomes AF: 0.241 AC: 60598 AN: 251416 Hom.: 9434 AF XY: 0.246 AC XY: 33483 AN XY: 135884

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.144

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.362

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.332 AC: 484628 AN: 1461300 Hom.: 88880 Cov.: 41 AF XY: 0.327 AC XY: 237509 AN XY: 726986

Gnomad4 AFR exome AF: 0.0629

Gnomad4 AMR exome AF: 0.148

Gnomad4 ASJ exome AF: 0.305

Gnomad4 EAS exome AF: 0.000706

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.214

Gnomad4 NFE exome AF: 0.382

Gnomad4 OTH exome AF: 0.299

GnomAD4 genome AF: 0.241 AC: 36631 AN: 152286 Hom.: 5892 Cov.: 32 AF XY: 0.229 AC XY: 17032 AN XY: 74462

Gnomad4 AFR AF: 0.0752

Gnomad4 AMR AF: 0.231

Gnomad4 ASJ AF: 0.310

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.371

Gnomad4 OTH AF: 0.232

Alfa AF: 0.321 Hom.: 6057

Bravo AF: 0.234

Asia WGS AF: 0.0820 AC: 289 AN: 3478

EpiCase AF: 0.355

EpiControl AF: 0.361

ClinVar

Significance: Benign

Submissions summary: Benign:10

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, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	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	Jul 14, 2021	- -

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:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -
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	-0.51
Cadd	Benign	13
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs9427714; hg19: chr1-201047111;