rs3767512

Positions:

chr1-201083155-G-A

Variant summary

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

The NM_000069.3(CACNA1S):c.1393+7C>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 0.0283 in 1,613,074 control chromosomes in the GnomAD database, including 1,712 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 0.028 ( 170 hom., cov: 33)

Exomes 𝑓: 0.028 ( 1542 hom. )

Consequence

CACNA1S
NM_000069.3 splice_region, intron

Scores

Splicing: ADA: 0.0002764

Clinical Significance

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

Conservation

PhyloP100: -1.28

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=-0.84).

BP6

Variant 1-201083155-G-A is Benign according to our data. Variant chr1-201083155-G-A is described in ClinVar as [Benign]. Clinvar id is 254792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201083155-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.172 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.1393+7C>T		splice_region_variant, intron_variant		ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 linkuse as main transcript	c.1393+7C>T		splice_region_variant, intron_variant			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.1393+7C>T		splice_region_variant, intron_variant		1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.0275

AC:

4187

AN:

152180

Hom.:

167

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00519

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0608

Gnomad ASJ

AF:

0.0550

Gnomad EAS

AF:

0.181

Gnomad SAS

AF:

0.0252

Gnomad FIN

AF:

0.0418

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0185

Gnomad OTH

AF:

0.0282

GnomAD3 exomes

AF:

0.0452

AC:

11277

AN:

249468

Hom.:

577

AF XY:

0.0409

AC XY:

5525

AN XY:

134994

show subpopulations

Gnomad AFR exome

AF:

0.00481

Gnomad AMR exome

AF:

0.107

Gnomad ASJ exome

AF:

0.0514

Gnomad EAS exome

AF:

0.170

Gnomad SAS exome

AF:

0.0207

Gnomad FIN exome

AF:

0.0429

Gnomad NFE exome

AF:

0.0192

Gnomad OTH exome

AF:

0.0317

GnomAD4 exome

AF:

0.0284

AC:

41511

AN:

1460776

Hom.:

1542

Cov.:

AF XY:

0.0281

AC XY:

20403

AN XY:

726648

show subpopulations

Gnomad4 AFR exome

AF:

0.00380

Gnomad4 AMR exome

AF:

0.102

Gnomad4 ASJ exome

AF:

0.0531

Gnomad4 EAS exome

AF:

0.211

Gnomad4 SAS exome

AF:

0.0215

Gnomad4 FIN exome

AF:

0.0402

Gnomad4 NFE exome

AF:

0.0190

Gnomad4 OTH exome

AF:

0.0302

GnomAD4 genome

AF:

0.0276

AC:

4203

AN:

152298

Hom.:

170

Cov.:

AF XY:

0.0300

AC XY:

2236

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00519

Gnomad4 AMR

AF:

0.0610

Gnomad4 ASJ

AF:

0.0550

Gnomad4 EAS

AF:

0.181

Gnomad4 SAS

AF:

0.0253

Gnomad4 FIN

AF:

0.0418

Gnomad4 NFE

AF:

0.0185

Gnomad4 OTH

AF:

0.0341

Alfa

AF:

0.0229

Hom.:

104

Bravo

AF:

0.0305

Asia WGS

AF:

0.0930

AC:

323

AN:

3478

EpiCase

AF:

0.0182

EpiControl

AF:

0.0169

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	GeneDx	Feb 26, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 28, 2021	- -

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	- -

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

-0.84

CADD

Benign

0.94

DANN

Benign

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00028

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