rs12029212

Positions:

• chr1-201052491-C-G
• chr1-201052491-C-T

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.3953+66G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,282,898 control chromosomes in the GnomAD database, including 32,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (9981 hom., cov: 31)
  • Exomes 𝑓: 0.18 (22148 hom.)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.975

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=-0.88).
• BP6: Variant 1-201052491-C-G is Benign according to our data. Variant chr1-201052491-C-G is described in ClinVar as [Benign]. Clinvar id is 678226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.3953+66G>C		intron_variant		ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.3896+66G>C		intron_variant			XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.3953+66G>C		intron_variant		1	NM_000069.3	ENSP00000355192	P2

Frequencies

GnomAD3 genomes AF: 0.298 AC: 44935 AN: 150860 Hom.: 9962 Cov.: 31

Gnomad AFR AF: 0.625

Gnomad AMI AF: 0.0759

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0932

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.246

GnomAD4 exome AF: 0.181 AC: 204950 AN: 1131918 Hom.: 22148 AF XY: 0.176 AC XY: 102006 AN XY: 578332

Gnomad4 AFR exome AF: 0.640

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.202

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.207

GnomAD4 genome AF: 0.298 AC: 44997 AN: 150980 Hom.: 9981 Cov.: 31 AF XY: 0.292 AC XY: 21574 AN XY: 73776

Gnomad4 AFR AF: 0.626

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.0929

Gnomad4 FIN AF: 0.205

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.242

Alfa AF: 0.0979 Hom.: 127

Bravo AF: 0.313

Asia WGS AF: 0.143 AC: 499 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.0
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs12029212; hg19: chr1-201021619;