rs1998721

Positions:

• chr1-201075620-A-G

Variant summary

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

The ENST00000362061.4(CACNA1S):​c.1828-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 1,613,192 control chromosomes in the GnomAD database, including 490,367 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40485 hom., cov: 33)
  • Exomes 𝑓: 0.78 (449882 hom.)
• Consequence: CACNA1S ENST00000362061.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006350
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.512

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=-0.9).
• BP6: Variant 1-201075620-A-G is Benign according to our data. Variant chr1-201075620-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 254804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201075620-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.1828-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.1828-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.1828-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000069.3	ENSP00000355192	P2

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109599 AN: 152054 Hom.: 40463 Cov.: 33

Gnomad AFR AF: 0.550

Gnomad AMI AF: 0.863

Gnomad AMR AF: 0.733

Gnomad ASJ AF: 0.786

Gnomad EAS AF: 0.961

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.708

GnomAD3 exomes AF: 0.782 AC: 196572 AN: 251416 Hom.: 77883 AF XY: 0.792 AC XY: 107610 AN XY: 135880

Gnomad AFR exome AF: 0.546

Gnomad AMR exome AF: 0.720

Gnomad ASJ exome AF: 0.782

Gnomad EAS exome AF: 0.960

Gnomad SAS exome AF: 0.890

Gnomad FIN exome AF: 0.780

Gnomad NFE exome AF: 0.776

Gnomad OTH exome AF: 0.782

GnomAD4 exome AF: 0.782 AC: 1143172 AN: 1461020 Hom.: 449882 Cov.: 45 AF XY: 0.786 AC XY: 571534 AN XY: 726850

Gnomad4 AFR exome AF: 0.542

Gnomad4 AMR exome AF: 0.723

Gnomad4 ASJ exome AF: 0.782

Gnomad4 EAS exome AF: 0.965

Gnomad4 SAS exome AF: 0.885

Gnomad4 FIN exome AF: 0.781

Gnomad4 NFE exome AF: 0.778

Gnomad4 OTH exome AF: 0.782

GnomAD4 genome AF: 0.721 AC: 109666 AN: 152172 Hom.: 40485 Cov.: 33 AF XY: 0.725 AC XY: 53961 AN XY: 74402

Gnomad4 AFR AF: 0.550

Gnomad4 AMR AF: 0.733

Gnomad4 ASJ AF: 0.786

Gnomad4 EAS AF: 0.961

Gnomad4 SAS AF: 0.899

Gnomad4 FIN AF: 0.788

Gnomad4 NFE AF: 0.776

Gnomad4 OTH AF: 0.712

Alfa AF: 0.764 Hom.: 37485

Bravo AF: 0.708

Asia WGS AF: 0.915 AC: 3179 AN: 3478

EpiCase AF: 0.767

EpiControl AF: 0.767

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 21, 2017	- -

Hypokalemic periodic paralysis, type 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 11, 2016	Variant summary: This c.1828-5T>C variant affects a non-conserved nucleotide, resulting in intronic change. 5/5 programs via Alamut predict that this variant does not affect normal splicing. This variant was found in 94859/121400 control chromosomes at a frequency of 0.7813756, which is more than 625099 times greater than the maximal expected frequency of a pathogenic allele (0.0000013) in this gene. This suggests that this variant is a very common polymorphism. -

Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 19, 2022

- -

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

Feb 01, 2024

- -

Malignant hyperthermia, susceptibility to, 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.36
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000063
dbscSNV1_RF	Benign	0.0020
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: rs1998721; hg19: chr1-201044748;