rs2297905

Positions:

chr1-201047518-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000069.3(CACNA1S):c.4543+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,607,216 control chromosomes in the GnomAD database, including 16,484 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3453 hom., cov: 33)

Exomes 𝑓: 0.13 ( 13031 hom. )

Consequence

CACNA1S
NM_000069.3 splice_region, intron

Scores

Splicing: ADA: 0.00002208

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.367

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=-0.82).

BP6

Variant 1-201047518-C-T is Benign according to our data. Variant chr1-201047518-C-T is described in ClinVar as [Benign]. Clinvar id is 254838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201047518-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.345 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.4543+7G>A		splice_region_variant, intron_variant		ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4 linkuse as main transcript	c.4486+7G>A		splice_region_variant, intron_variant			XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.4543+7G>A		splice_region_variant, intron_variant		1	NM_000069.3	ENSP00000355192	P2

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28224

AN:

152040

Hom.:

3446

Cov.:

show subpopulations

Gnomad AFR

AF:

0.350

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.132

Gnomad ASJ

AF:

0.0948

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.0613

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.125

Gnomad OTH

AF:

0.159

GnomAD3 exomes

AF:

0.127

AC:

31937

AN:

251082

Hom.:

2626

AF XY:

0.121

AC XY:

16473

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.359

Gnomad AMR exome

AF:

0.0733

Gnomad ASJ exome

AF:

0.0991

Gnomad EAS exome

AF:

0.133

Gnomad SAS exome

AF:

0.0645

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.126

Gnomad OTH exome

AF:

0.135

GnomAD4 exome

AF:

0.127

AC:

184448

AN:

1455058

Hom.:

13031

Cov.:

AF XY:

0.124

AC XY:

90034

AN XY:

724256

show subpopulations

Gnomad4 AFR exome

AF:

0.357

Gnomad4 AMR exome

AF:

0.0790

Gnomad4 ASJ exome

AF:

0.0989

Gnomad4 EAS exome

AF:

0.127

Gnomad4 SAS exome

AF:

0.0649

Gnomad4 FIN exome

AF:

0.139

Gnomad4 NFE exome

AF:

0.126

Gnomad4 OTH exome

AF:

0.136

GnomAD4 genome

AF:

0.186

AC:

28256

AN:

152158

Hom.:

3453

Cov.:

AF XY:

0.182

AC XY:

13548

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.350

Gnomad4 AMR

AF:

0.132

Gnomad4 ASJ

AF:

0.0948

Gnomad4 EAS

AF:

0.126

Gnomad4 SAS

AF:

0.0609

Gnomad4 FIN

AF:

0.146

Gnomad4 NFE

AF:

0.125

Gnomad4 OTH

AF:

0.156

Alfa

AF:

0.134

Hom.:

2580

Bravo

AF:

0.195

Asia WGS

AF:

0.115

AC:

398

AN:

3478

EpiCase

AF:

0.119

EpiControl

AF:

0.122

ClinVar

Significance: Benign

Submissions summary: Benign:10

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 29, 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 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

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

- -

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

-0.82

CADD

Benign

1.8

DANN

Benign

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.0

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