rs3767512

chr1-201083155-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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:9
• Conservation: PhyloP100: -1.28

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=-0.84).
• 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	UniProt
CACNA1S	NM_000069.3	c.1393+7C>T		splice_region_variant, intron_variant		ENST00000362061.4
CACNA1S	XM_005245478.4	c.1393+7C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4	c.1393+7C>T		splice_region_variant, intron_variant		1	NM_000069.3	P2

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4187 AN: 152180 Hom.: 167 Cov.: 33

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

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.: 31 AF XY: 0.0281 AC XY: 20403 AN XY: 726648

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.: 33 AF XY: 0.0300 AC XY: 2236 AN XY: 74462

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

Hypokalemic periodic paralysis, type 1 Benign:2

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

Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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 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

Other links and lift over

dbSNP: rs3767512; hg19: chr1-201052283; COSMIC: COSV62943211;