rs113792034

Positions:

• chr1-201065959-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000069.3(CACNA1S):​c.2746-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0406 in 1,571,438 control chromosomes in the GnomAD database, including 1,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (120 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1330 hom.)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.848

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-201065959-G-A is Benign according to our data. Variant chr1-201065959-G-A is described in ClinVar as [Benign]. Clinvar id is 254821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201065959-G-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.2746-14C>T		intron_variant		ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.2746-14C>T		intron_variant			XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.2746-14C>T		intron_variant		1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes AF: 0.0374 AC: 5698 AN: 152190 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0211

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.0559

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0411

GnomAD3 exomes AF: 0.0367 AC: 8748 AN: 238478 Hom.: 196 AF XY: 0.0370 AC XY: 4774 AN XY: 128910

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.000683

Gnomad SAS exome AF: 0.0303

Gnomad FIN exome AF: 0.0557

Gnomad NFE exome AF: 0.0473

Gnomad OTH exome AF: 0.0422

GnomAD4 exome AF: 0.0409 AC: 58056 AN: 1419130 Hom.: 1330 Cov.: 26 AF XY: 0.0405 AC XY: 28647 AN XY: 707868

Gnomad4 AFR exome AF: 0.0299

Gnomad4 AMR exome AF: 0.0205

Gnomad4 ASJ exome AF: 0.0234

Gnomad4 EAS exome AF: 0.000204

Gnomad4 SAS exome AF: 0.0302

Gnomad4 FIN exome AF: 0.0540

Gnomad4 NFE exome AF: 0.0441

Gnomad4 OTH exome AF: 0.0393

GnomAD4 genome AF: 0.0374 AC: 5698 AN: 152308 Hom.: 120 Cov.: 32 AF XY: 0.0374 AC XY: 2782 AN XY: 74482

Gnomad4 AFR AF: 0.0333

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.0211

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.0559

Gnomad4 NFE AF: 0.0456

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.0394 Hom.: 31

Bravo AF: 0.0333

Asia WGS AF: 0.0150 AC: 53 AN: 3478

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	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 29, 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	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	- -

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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.0
DANN	Benign	0.67

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: rs113792034; hg19: chr1-201035087;