rs56021911

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000069.3(CACNA1S):c.3525+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,535,186 control chromosomes in the GnomAD database, including 355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 26 hom., cov: 33)

Exomes 𝑓: 0.020 ( 329 hom. )

Consequence

CACNA1S
NM_000069.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.277

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 1-201059171-G-A is Benign according to our data. Variant chr1-201059171-G-A is described in ClinVar as [Benign]. Clinvar id is 254826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201059171-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0151 (2307/152284) while in subpopulation NFE AF= 0.0227 (1542/68026). AF 95% confidence interval is 0.0217. There are 26 homozygotes in gnomad4. There are 1147 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 26 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.3525+18C>T		intron_variant	Intron 27 of 43	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 link	c.3525+18C>T		intron_variant	Intron 27 of 42		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 link	c.3525+18C>T		intron_variant	Intron 27 of 43	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2308

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00456

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.00910

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0330

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0227

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.0145

AC:

3630

AN:

250114

Hom.:

AF XY:

0.0146

AC XY:

1972

AN XY:

135144

show subpopulations

Gnomad AFR exome

AF:

0.00297

Gnomad AMR exome

AF:

0.00548

Gnomad ASJ exome

AF:

0.00676

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00204

Gnomad FIN exome

AF:

0.0300

Gnomad NFE exome

AF:

0.0223

Gnomad OTH exome

AF:

0.0157

GnomAD4 exome

AF:

0.0203

AC:

28125

AN:

1382902

Hom.:

329

Cov.:

AF XY:

0.0199

AC XY:

13751

AN XY:

692292

show subpopulations

Gnomad4 AFR exome

AF:

0.00285

Gnomad4 AMR exome

AF:

0.00597

Gnomad4 ASJ exome

AF:

0.00917

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00197

Gnomad4 FIN exome

AF:

0.0300

Gnomad4 NFE exome

AF:

0.0238

Gnomad4 OTH exome

AF:

0.0178

GnomAD4 genome

AF:

0.0151

AC:

2307

AN:

152284

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1147

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00455

Gnomad4 AMR

AF:

0.00902

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0330

Gnomad4 NFE

AF:

0.0227

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.0197

Hom.:

Bravo

AF:

0.0132

Asia WGS

AF:

0.000577

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:3

Mar 03, 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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1

Benign:1

Aug 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypokalemic periodic paralysis, type 1

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant hyperthermia, susceptibility to, 5

Benign:1

Apr 11, 2023

Genome-Nilou Lab

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

-0.92

CADD

Benign

0.66

DANN

Benign

0.60

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

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