rs41267501

chr1-201061931-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000069.3(CACNA1S):c.3053+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,614,082 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 19 hom., cov: 33)

Exomes 𝑓: 0.017 ( 278 hom. )

Consequence

CACNA1S
NM_000069.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.979

Variant links:

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]

CACNA1S links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 1-201061931-A-G is Benign according to our data. Variant chr1-201061931-A-G is described in ClinVar as [Benign]. Clinvar id is 254824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201061931-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0134 (2038/152350) while in subpopulation SAS AF= 0.0377 (182/4826). AF 95% confidence interval is 0.0332. There are 19 homozygotes in gnomad4. There are 1050 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 19 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1S	NM_000069.3 linkuse as main transcript	c.3053+13T>C		intron_variant		ENST00000362061.4
CACNA1S	XM_005245478.4 linkuse as main transcript	c.3053+13T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.3053+13T>C		intron_variant		1	NM_000069.3	P2

Frequencies

GnomAD3 genomes

AF:

0.0134

AC:

2039

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0126

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0377

Gnomad FIN

AF:

0.0232

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0167

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0178

AC:

4483

AN:

251250

Hom.:

AF XY:

0.0195

AC XY:

2646

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.00796

Gnomad ASJ exome

AF:

0.0253

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0370

Gnomad FIN exome

AF:

0.0252

Gnomad NFE exome

AF:

0.0184

Gnomad OTH exome

AF:

0.0209

GnomAD4 exome

AF:

0.0170

AC:

24836

AN:

1461732

Hom.:

278

Cov.:

AF XY:

0.0179

AC XY:

13019

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00290

Gnomad4 AMR exome

AF:

0.00861

Gnomad4 ASJ exome

AF:

0.0234

Gnomad4 EAS exome

AF:

0.000327

Gnomad4 SAS exome

AF:

0.0360

Gnomad4 FIN exome

AF:

0.0231

Gnomad4 NFE exome

AF:

0.0163

Gnomad4 OTH exome

AF:

0.0172

GnomAD4 genome

AF:

0.0134

AC:

2038

AN:

152350

Hom.:

Cov.:

AF XY:

0.0141

AC XY:

1050

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00291

Gnomad4 AMR

AF:

0.0125

Gnomad4 ASJ

AF:

0.0219

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0377

Gnomad4 FIN

AF:

0.0232

Gnomad4 NFE

AF:

0.0167

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0166

Hom.:

Bravo

AF:

0.0117

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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 13, 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	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

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

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 27, 2023

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Malignant hyperthermia, susceptibility to, 5

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

-0.86

Cadd

Benign

6.1

Dann

Benign

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: -30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over