rs113558244

Positions:

• chr1-201112171-C-G
• chr1-201112171-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.152+17G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,609,462 control chromosomes in the GnomAD database, including 740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (270 hom., cov: 30)
  • Exomes 𝑓: 0.0083 (470 hom.)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.90

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 1-201112171-C-G is Benign according to our data. Variant chr1-201112171-C-G is described in ClinVar as [Benign]. Clinvar id is 254798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201112171-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.152+17G>C		intron_variant		ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.152+17G>C		intron_variant			XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.152+17G>C		intron_variant		1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 5132 AN: 151712 Hom.: 263 Cov.: 30

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0313

Gnomad SAS AF: 0.0597

Gnomad FIN AF: 0.00547

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000780

Gnomad OTH AF: 0.0188

GnomAD3 exomes AF: 0.0188 AC: 4703 AN: 250092 Hom.: 180 AF XY: 0.0193 AC XY: 2615 AN XY: 135286

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.00481

Gnomad ASJ exome AF: 0.00190

Gnomad EAS exome AF: 0.0311

Gnomad SAS exome AF: 0.0600

Gnomad FIN exome AF: 0.00574

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00829 AC: 12087 AN: 1457636 Hom.: 470 Cov.: 33 AF XY: 0.00945 AC XY: 6847 AN XY: 724352

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.00533

Gnomad4 ASJ exome AF: 0.00173

Gnomad4 EAS exome AF: 0.0262

Gnomad4 SAS exome AF: 0.0571

Gnomad4 FIN exome AF: 0.00602

Gnomad4 NFE exome AF: 0.000557

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0340 AC: 5160 AN: 151826 Hom.: 270 Cov.: 30 AF XY: 0.0340 AC XY: 2526 AN XY: 74220

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.0314

Gnomad4 SAS AF: 0.0591

Gnomad4 FIN AF: 0.00547

Gnomad4 NFE AF: 0.000780

Gnomad4 OTH AF: 0.0200

Alfa AF: 0.00515 Hom.: 3

Bravo AF: 0.0369

Asia WGS AF: 0.0640 AC: 222 AN: 3476

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	GeneDx	Mar 24, 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	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -

Hypokalemic periodic paralysis, type 1 Benign:1

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

- -

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

- -

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	0.0010
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs113558244; hg19: chr1-201081299;