rs1546416

chr1-201040428-A-G

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.5227-54T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,602,084 control chromosomes in the GnomAD database, including 98,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10014 hom., cov: 33)
  • Exomes 𝑓: 0.35 (88237 hom.)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.347

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-201040428-A-G is Benign according to our data. Variant chr1-201040428-A-G is described in ClinVar as [Benign]. Clinvar id is 678243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201040428-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1S	NM_000069.3	c.5227-54T>C		intron_variant		ENST00000362061.4
LOC101929305	XR_922410.3	n.1378-1427A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4	c.5227-54T>C		intron_variant		1	NM_000069.3	P2
	ENST00000415359.1	n.211-1427A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54438 AN: 152026 Hom.: 9989 Cov.: 33

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.336

GnomAD4 exome AF: 0.347 AC: 503038 AN: 1449940 Hom.: 88237 Cov.: 32 AF XY: 0.344 AC XY: 247925 AN XY: 721354

Gnomad4 AFR exome AF: 0.415

Gnomad4 AMR exome AF: 0.312

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.285

Gnomad4 SAS exome AF: 0.266

Gnomad4 FIN exome AF: 0.323

Gnomad4 NFE exome AF: 0.355

Gnomad4 OTH exome AF: 0.344

GnomAD4 genome AF: 0.358 AC: 54508 AN: 152144 Hom.: 10014 Cov.: 33 AF XY: 0.355 AC XY: 26437 AN XY: 74368

Gnomad4 AFR AF: 0.416

Gnomad4 AMR AF: 0.294

Gnomad4 ASJ AF: 0.359

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.262

Gnomad4 FIN AF: 0.322

Gnomad4 NFE AF: 0.353

Gnomad4 OTH AF: 0.342

Alfa AF: 0.351 Hom.: 12310

Bravo AF: 0.361

Asia WGS AF: 0.308 AC: 1073 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypokalemic periodic paralysis, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 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	-0.89
Cadd	Benign	0.90
Dann	Benign	0.53

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: rs1546416; hg19: chr1-201009556; COSMIC: COSV62945146; COSMIC: COSV62945146;