rs16847674

chr1-201078007-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000069.3(CACNA1S):c.1491C>T(p.Asn497=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0656 in 1,614,036 control chromosomes in the GnomAD database, including 4,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (902 hom., cov: 31)
  • Exomes 𝑓: 0.063 (3867 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.27

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-201078007-G-A is Benign according to our data. Variant chr1-201078007-G-A is described in ClinVar as [Benign]. Clinvar id is 254795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201078007-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1S	NM_000069.3	c.1491C>T	p.Asn497=	synonymous_variant	11/44	ENST00000362061.4
CACNA1S	XM_005245478.4	c.1491C>T	p.Asn497=	synonymous_variant	11/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4	c.1491C>T	p.Asn497=	synonymous_variant	11/44	1	NM_000069.3	P2

Frequencies

GnomAD3 genomes AF: 0.0951 AC: 14472 AN: 152156 Hom.: 897 Cov.: 31

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0864

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.0563

Gnomad FIN AF: 0.0967

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0502

Gnomad OTH AF: 0.0883

GnomAD3 exomes AF: 0.0872 AC: 21936 AN: 251492 Hom.: 1217 AF XY: 0.0819 AC XY: 11133 AN XY: 135922

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.0865

Gnomad EAS exome AF: 0.183

Gnomad SAS exome AF: 0.0614

Gnomad FIN exome AF: 0.0965

Gnomad NFE exome AF: 0.0538

Gnomad OTH exome AF: 0.0721

GnomAD4 exome AF: 0.0625 AC: 91377 AN: 1461762 Hom.: 3867 Cov.: 35 AF XY: 0.0621 AC XY: 45127 AN XY: 727176

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.131

Gnomad4 ASJ exome AF: 0.0893

Gnomad4 EAS exome AF: 0.219

Gnomad4 SAS exome AF: 0.0607

Gnomad4 FIN exome AF: 0.0918

Gnomad4 NFE exome AF: 0.0483

Gnomad4 OTH exome AF: 0.0718

GnomAD4 genome AF: 0.0953 AC: 14511 AN: 152274 Hom.: 902 Cov.: 31 AF XY: 0.0977 AC XY: 7274 AN XY: 74462

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.0864

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.0563

Gnomad4 FIN AF: 0.0967

Gnomad4 NFE AF: 0.0502

Gnomad4 OTH AF: 0.0936

Alfa AF: 0.0750 Hom.: 351

Bravo AF: 0.101

Asia WGS AF: 0.123 AC: 427 AN: 3478

EpiCase AF: 0.0574

EpiControl AF: 0.0559

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 5 Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 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	- -

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	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	9.7
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs16847674; hg19: chr1-201047135; COSMIC: COSV62939562;