rs79984703

chr1-201074499-C-A

Variant summary

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

The NM_000069.3(CACNA1S):c.2063+7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,574,482 control chromosomes in the GnomAD database, including 858 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 0.024 ( 72 hom., cov: 34)

Exomes 𝑓: 0.029 ( 786 hom. )

Consequence

CACNA1S
NM_000069.3 splice_region, intron

Scores

Splicing: ADA: 0.0004475

Clinical Significance

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

Conservation

PhyloP100: -0.308

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=-0.7).

BP6

Variant 1-201074499-C-A is Benign according to our data. Variant chr1-201074499-C-A is described in ClinVar as [Benign]. Clinvar id is 254810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201074499-C-A is described in Lovd as [Likely_benign]. Variant chr1-201074499-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0238 (3623/152362) while in subpopulation NFE AF= 0.0319 (2169/68022). AF 95% confidence interval is 0.0308. There are 72 homozygotes in gnomad4. There are 1888 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 72 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1S	NM_000069.3 linkuse as main transcript	c.2063+7G>T		splice_region_variant, intron_variant		ENST00000362061.4
CACNA1S	XM_005245478.4 linkuse as main transcript	c.2063+7G>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.2063+7G>T		splice_region_variant, intron_variant		1	NM_000069.3	P2

Frequencies

GnomAD3 genomes

AF:

0.0238

AC:

3629

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00646

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0225

Gnomad FIN

AF:

0.0734

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0319

Gnomad OTH

AF:

0.0181

GnomAD3 exomes

AF:

0.0257

AC:

6411

AN:

249350

Hom.:

129

AF XY:

0.0268

AC XY:

3606

AN XY:

134732

show subpopulations

Gnomad AFR exome

AF:

0.00561

Gnomad AMR exome

AF:

0.00889

Gnomad ASJ exome

AF:

0.00810

Gnomad EAS exome

AF:

0.000382

Gnomad SAS exome

AF:

0.0261

Gnomad FIN exome

AF:

0.0666

Gnomad NFE exome

AF:

0.0315

Gnomad OTH exome

AF:

0.0249

GnomAD4 exome

AF:

0.0294

AC:

41831

AN:

1422120

Hom.:

786

Cov.:

AF XY:

0.0295

AC XY:

20943

AN XY:

709696

show subpopulations

Gnomad4 AFR exome

AF:

0.00652

Gnomad4 AMR exome

AF:

0.00906

Gnomad4 ASJ exome

AF:

0.00843

Gnomad4 EAS exome

AF:

0.000253

Gnomad4 SAS exome

AF:

0.0274

Gnomad4 FIN exome

AF:

0.0632

Gnomad4 NFE exome

AF:

0.0313

Gnomad4 OTH exome

AF:

0.0250

GnomAD4 genome

AF:

0.0238

AC:

3623

AN:

152362

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1888

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00644

Gnomad4 AMR

AF:

0.0102

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0222

Gnomad4 FIN

AF:

0.0734

Gnomad4 NFE

AF:

0.0319

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0291

Hom.:

Bravo

AF:

0.0186

Asia WGS

AF:

0.0100

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:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Athena Diagnostics	Jul 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 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	Apr 11, 2023	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

- -

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

Benign:1

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

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

Cadd

Benign

1.6

Dann

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00045

dbscSNV1_RF

Benign

0.032

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