rs191758096

Positions:

• chr1-201053456-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000069.3(CACNA1S):​c.3795+3G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,614,124 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (14 hom.)
• Consequence: CACNA1S NM_000069.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0003253
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.645

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-201053456-C-T is Benign according to our data. Variant chr1-201053456-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 254827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201053456-C-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00128 (195/152248) while in subpopulation SAS AF= 0.00538 (26/4830). AF 95% confidence interval is 0.00377. There are 1 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 14 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.3795+3G>A		splice_donor_region_variant, intron_variant		ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.3738+3G>A		splice_donor_region_variant, intron_variant			XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.3795+3G>A		splice_donor_region_variant, intron_variant		1	NM_000069.3	ENSP00000355192	P2

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00198 AC: 497 AN: 251402 Hom.: 5 AF XY: 0.00225 AC XY: 306 AN XY: 135882

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00480

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00171 AC: 2494 AN: 1461876 Hom.: 14 Cov.: 35 AF XY: 0.00187 AC XY: 1362 AN XY: 727242

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00865

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00486

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74438

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00538

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00178 Hom.: 0

Bravo AF: 0.00141

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2015	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	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Sep 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 02, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Jun 26, 2017	BS1,BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -

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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CACNA1S: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Malignant hyperthermia, susceptibility to, 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 20, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Congenital myopathy 18 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Thyrotoxic periodic paralysis, susceptibility to, 1 Benign:1

Likely 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00033
dbscSNV1_RF	Benign	0.050
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

Other links and lift over

dbSNP: rs191758096; hg19: chr1-201022584;