Variant rs4915476 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000069.3(CACNA1S):c.1564C>T(p.Leu522Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.215 in 1,613,632 control chromosomes in the GnomAD database, including 39,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4049 hom., cov: 33)

Exomes 𝑓: 0.21 ( 35189 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.91

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 1-201077934-G-A is Benign according to our data. Variant chr1-201077934-G-A is described in ClinVar as [Benign]. Clinvar id is 254801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201077934-G-A is described in Lovd as [Pathogenic]. Variant chr1-201077934-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3 linkuse as main transcript	c.1564C>T	p.Leu522Leu	synonymous_variant	11/44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 linkuse as main transcript	c.1564C>T	p.Leu522Leu	synonymous_variant	11/43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.1564C>T	p.Leu522Leu	synonymous_variant	11/44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.225

AC:

34218

AN:

152086

Hom.:

4045

Cov.:

show subpopulations

Gnomad AFR

AF:

0.259

Gnomad AMI

AF:

0.285

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.221

Gnomad EAS

AF:

0.0402

Gnomad SAS

AF:

0.101

Gnomad FIN

AF:

0.217

Gnomad MID

AF:

0.283

Gnomad NFE

AF:

0.221

Gnomad OTH

AF:

0.263

GnomAD3 exomes

AF:

0.209

AC:

52602

AN:

251284

Hom.:

6171

AF XY:

0.205

AC XY:

27833

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.259

Gnomad AMR exome

AF:

0.275

Gnomad ASJ exome

AF:

0.229

Gnomad EAS exome

AF:

0.0403

Gnomad SAS exome

AF:

0.112

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.229

Gnomad OTH exome

AF:

0.223

GnomAD4 exome

AF:

0.214

AC:

313111

AN:

1461428

Hom.:

35189

Cov.:

AF XY:

0.211

AC XY:

153600

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.255

Gnomad4 AMR exome

AF:

0.270

Gnomad4 ASJ exome

AF:

0.229

Gnomad4 EAS exome

AF:

0.0363

Gnomad4 SAS exome

AF:

0.113

Gnomad4 FIN exome

AF:

0.236

Gnomad4 NFE exome

AF:

0.224

Gnomad4 OTH exome

AF:

0.208

GnomAD4 genome

AF:

0.225

AC:

34246

AN:

152204

Hom.:

4049

Cov.:

AF XY:

0.221

AC XY:

16476

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.259

Gnomad4 AMR

AF:

0.248

Gnomad4 ASJ

AF:

0.221

Gnomad4 EAS

AF:

0.0403

Gnomad4 SAS

AF:

0.0998

Gnomad4 FIN

AF:

0.217

Gnomad4 NFE

AF:

0.221

Gnomad4 OTH

AF:

0.260

Alfa

AF:

0.188

Hom.:

946

Bravo

AF:

0.232

Asia WGS

AF:

0.0740

AC:

258

AN:

3478

EpiCase

AF:

0.238

EpiControl

AF:

0.247

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 28, 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	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Malignant hyperthermia, susceptibility to, 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -

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

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

8.7

DANN

Benign

0.75

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