rs1998721

Variant names:

• chr1-201075620-A-G
• rs1998721
• NM_000069.3:c.1828-5T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000069.3(CACNA1S):​c.1828-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 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 NM_000069.3 splice_region, intron
• Scores: Splicing: ADA: 0.00006350
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.512
• Publications: 20 publications found

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]

CACNA1S Gene-Disease associations (from GenCC):

• congenital myopathy 18

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypokalemic periodic paralysis, type 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• malignant hyperthermia, susceptibility to, 5

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital myopathy

  Inheritance: SD, AR, AD Classification: STRONG Submitted by: Illumina, Genomics England PanelApp
• hypokalemic periodic paralysis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 254804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.1828-5T>C		splice_region_variant, intron_variant	Intron 12 of 43	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.1828-5T>C		splice_region_variant, intron_variant	Intron 12 of 42		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.1828-5T>C		splice_region_variant, intron_variant	Intron 12 of 43	1	NM_000069.3	ENSP00000355192.3

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

GnomAD2 exomes AF: 0.782 AC: 196572 AN: 251416 AF XY: 0.792

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 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

African (AFR) AF: 0.542 AC: 18141 AN: 33450

American (AMR) AF: 0.723 AC: 32353 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20426 AN: 26116

East Asian (EAS) AF: 0.965 AC: 38285 AN: 39690

South Asian (SAS) AF: 0.885 AC: 76359 AN: 86250

European-Finnish (FIN) AF: 0.781 AC: 41731 AN: 53418

Middle Eastern (MID) AF: 0.760 AC: 4380 AN: 5764

European-Non Finnish (NFE) AF: 0.778 AC: 864256 AN: 1111238

Other (OTH) AF: 0.782 AC: 47241 AN: 60376

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

African (AFR) AF: 0.550 AC: 22809 AN: 41494

American (AMR) AF: 0.733 AC: 11216 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.786 AC: 2729 AN: 3472

East Asian (EAS) AF: 0.961 AC: 4974 AN: 5178

South Asian (SAS) AF: 0.899 AC: 4335 AN: 4824

European-Finnish (FIN) AF: 0.788 AC: 8342 AN: 10592

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.776 AC: 52764 AN: 67996

Other (OTH) AF: 0.712 AC: 1505 AN: 2114

Alfa AF: 0.756 Hom.: 45807

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

Jul 21, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 22, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 11, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant hyperthermia, susceptibility to, 5 Benign:1

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.36
DANN	Benign	0.42
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1998721; hg19: chr1-201044748;