rs12742169

chr1-201083182-A-T

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.1373T>A(p.Leu458His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,613,504 control chromosomes in the GnomAD database, including 94,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5762 hom., cov: 33)
  • Exomes 𝑓: 0.33 (88432 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.19

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 (MetaRNN=0.004697144).
• BP6: Variant 1-201083182-A-T is Benign according to our data. Variant chr1-201083182-A-T is described in ClinVar as [Benign]. Clinvar id is 254789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201083182-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1S	NM_000069.3	c.1373T>A	p.Leu458His	missense_variant	10/44	ENST00000362061.4
CACNA1S	XM_005245478.4	c.1373T>A	p.Leu458His	missense_variant	10/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4	c.1373T>A	p.Leu458His	missense_variant	10/44	1	NM_000069.3	P2

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36303 AN: 151934 Hom.: 5759 Cov.: 33

Gnomad AFR AF: 0.0729

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.236

GnomAD3 exomes AF: 0.239 AC: 60095 AN: 251056 Hom.: 9156 AF XY: 0.245 AC XY: 33189 AN XY: 135682

Gnomad AFR exome AF: 0.0648

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.000491

Gnomad SAS exome AF: 0.144

Gnomad FIN exome AF: 0.205

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.331 AC: 483449 AN: 1461452 Hom.: 88432 Cov.: 46 AF XY: 0.326 AC XY: 236918 AN XY: 727040

Gnomad4 AFR exome AF: 0.0600

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.302

Gnomad4 EAS exome AF: 0.000781

Gnomad4 SAS exome AF: 0.142

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.381

Gnomad4 OTH exome AF: 0.297

GnomAD4 genome AF: 0.239 AC: 36307 AN: 152052 Hom.: 5762 Cov.: 33 AF XY: 0.227 AC XY: 16912 AN XY: 74352

Gnomad4 AFR AF: 0.0729

Gnomad4 AMR AF: 0.231

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.134

Gnomad4 FIN AF: 0.207

Gnomad4 NFE AF: 0.368

Gnomad4 OTH AF: 0.233

Alfa AF: 0.334 Hom.: 6894

Bravo AF: 0.233

TwinsUK AF: 0.383 AC: 1419

ALSPAC AF: 0.369 AC: 1423

ESP6500AA AF: 0.0765 AC: 337

ESP6500EA AF: 0.376 AC: 3235

ExAC AF: 0.243 AC: 29529

Asia WGS AF: 0.0820 AC: 289 AN: 3478

EpiCase AF: 0.353

EpiControl AF: 0.357

ClinVar

Significance: Benign

Submissions summary: Benign:9

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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. -

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:1

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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	21
Dann	Benign	0.93
DEOGEN2	Benign	0.32	T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.36	T;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	1.7	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.22	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.83	.;P
Vest4		0.15
MPC		0.21
ClinPred		0.062	T
GERP RS		3.4
Varity_R		0.21
gMVP		0.39

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: rs12742169; hg19: chr1-201052310; COSMIC: COSV62940938;