rs56183942

Variant names:

• chr1-201053248-G-A
• rs56183942
• NM_000069.3:c.3822C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000069.3(CACNA1S):​c.3822C>T​(p.Ile1274Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,614,218 control chromosomes in the GnomAD database, including 1,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (141 hom., cov: 32)
  • Exomes 𝑓: 0.020 (943 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.611

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 1-201053248-G-A is Benign according to our data. Variant chr1-201053248-G-A is described in ClinVar as [Benign]. Clinvar id is 254831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201053248-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.611 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.3822C>T	p.Ile1274Ile	synonymous_variant	Exon 31 of 44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.3765C>T	p.Ile1255Ile	synonymous_variant	Exon 30 of 43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.3822C>T	p.Ile1274Ile	synonymous_variant	Exon 31 of 44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3311 AN: 152236 Hom.: 137 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0382

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.0438

Gnomad FIN AF: 0.00593

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0320

GnomAD3 exomes AF: 0.0370 AC: 9299 AN: 251396 Hom.: 434 AF XY: 0.0353 AC XY: 4798 AN XY: 135896

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.0727

Gnomad ASJ exome AF: 0.0269

Gnomad EAS exome AF: 0.172

Gnomad SAS exome AF: 0.0422

Gnomad FIN exome AF: 0.00776

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0204 AC: 29863 AN: 1461864 Hom.: 943 Cov.: 34 AF XY: 0.0210 AC XY: 15238 AN XY: 727234

Gnomad4 AFR exome AF: 0.0140

Gnomad4 AMR exome AF: 0.0705

Gnomad4 ASJ exome AF: 0.0280

Gnomad4 EAS exome AF: 0.171

Gnomad4 SAS exome AF: 0.0422

Gnomad4 FIN exome AF: 0.00779

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.0256

GnomAD4 genome AF: 0.0219 AC: 3335 AN: 152354 Hom.: 141 Cov.: 32 AF XY: 0.0228 AC XY: 1701 AN XY: 74498

Gnomad4 AFR AF: 0.0128

Gnomad4 AMR AF: 0.0382

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.0443

Gnomad4 FIN AF: 0.00593

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0160 Hom.: 13

Bravo AF: 0.0261

Asia WGS AF: 0.108 AC: 376 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 5 Benign:3

Mar 28, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Mar 18, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypokalemic periodic paralysis, type 1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Oct 30, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital myopathy 18 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thyrotoxic periodic paralysis, susceptibility to, 1 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs56183942; hg19: chr1-201022376; COSMIC: COSV62937039;