rs2296383

chr1-201091737-G-A

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.597C>T(p.Ile199=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 1,613,646 control chromosomes in the GnomAD database, including 143,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9766 hom., cov: 32)
  • Exomes 𝑓: 0.42 (134092 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.711

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 1-201091737-G-A is Benign according to our data. Variant chr1-201091737-G-A is described in ClinVar as [Benign]. Clinvar id is 254852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201091737-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.711 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1S	NM_000069.3	c.597C>T	p.Ile199=	synonymous_variant	5/44	ENST00000362061.4
CACNA1S	XM_005245478.4	c.597C>T	p.Ile199=	synonymous_variant	5/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4	c.597C>T	p.Ile199=	synonymous_variant	5/44	1	NM_000069.3	P2

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49894 AN: 152006 Hom.: 9768 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.337

GnomAD3 exomes AF: 0.390 AC: 97845 AN: 251092 Hom.: 20091 AF XY: 0.400 AC XY: 54289 AN XY: 135698

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.350

Gnomad ASJ exome AF: 0.464

Gnomad EAS exome AF: 0.359

Gnomad SAS exome AF: 0.451

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.393

GnomAD4 exome AF: 0.424 AC: 619082 AN: 1461522 Hom.: 134092 Cov.: 44 AF XY: 0.426 AC XY: 309402 AN XY: 727056

Gnomad4 AFR exome AF: 0.0957

Gnomad4 AMR exome AF: 0.352

Gnomad4 ASJ exome AF: 0.465

Gnomad4 EAS exome AF: 0.389

Gnomad4 SAS exome AF: 0.450

Gnomad4 FIN exome AF: 0.373

Gnomad4 NFE exome AF: 0.438

Gnomad4 OTH exome AF: 0.412

GnomAD4 genome AF: 0.328 AC: 49904 AN: 152124 Hom.: 9766 Cov.: 32 AF XY: 0.327 AC XY: 24294 AN XY: 74364

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.453

Gnomad4 EAS AF: 0.367

Gnomad4 SAS AF: 0.438

Gnomad4 FIN AF: 0.363

Gnomad4 NFE AF: 0.433

Gnomad4 OTH AF: 0.339

Alfa AF: 0.408 Hom.: 21598

Bravo AF: 0.315

Asia WGS AF: 0.394 AC: 1371 AN: 3478

EpiCase AF: 0.430

EpiControl AF: 0.425

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 21, 2017	- -

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 Benign:2

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	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 11, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	6.7
Dann	Benign	0.76

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: rs2296383; hg19: chr1-201060865; COSMIC: COSV62936330;