rs79984703

Variant names:

• chr1-201074499-C-A
• rs79984703
• NM_000069.3:c.2063+7G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000069.3(CACNA1S):​c.2063+7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,574,482 control chromosomes in the GnomAD database, including 858 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (72 hom., cov: 34)
  • Exomes 𝑓: 0.029 (786 hom.)
• Consequence: CACNA1S NM_000069.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004475
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.308

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=-0.7).
• BP6: Variant 1-201074499-C-A is Benign according to our data. Variant chr1-201074499-C-A is described in ClinVar as [Benign]. Clinvar id is 254810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201074499-C-A is described in Lovd as [Likely_benign]. Variant chr1-201074499-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0238 (3623/152362) while in subpopulation NFE AF= 0.0319 (2169/68022). AF 95% confidence interval is 0.0308. There are 72 homozygotes in gnomad4. There are 1888 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 72 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.2063+7G>T		splice_region_variant, intron_variant	Intron 14 of 43	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.2063+7G>T		splice_region_variant, intron_variant	Intron 14 of 42		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.2063+7G>T		splice_region_variant, intron_variant	Intron 14 of 43	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3629 AN: 152244 Hom.: 72 Cov.: 34

Gnomad AFR AF: 0.00646

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0225

Gnomad FIN AF: 0.0734

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0181

GnomAD3 exomes AF: 0.0257 AC: 6411 AN: 249350 Hom.: 129 AF XY: 0.0268 AC XY: 3606 AN XY: 134732

Gnomad AFR exome AF: 0.00561

Gnomad AMR exome AF: 0.00889

Gnomad ASJ exome AF: 0.00810

Gnomad EAS exome AF: 0.000382

Gnomad SAS exome AF: 0.0261

Gnomad FIN exome AF: 0.0666

Gnomad NFE exome AF: 0.0315

Gnomad OTH exome AF: 0.0249

GnomAD4 exome AF: 0.0294 AC: 41831 AN: 1422120 Hom.: 786 Cov.: 27 AF XY: 0.0295 AC XY: 20943 AN XY: 709696

Gnomad4 AFR exome AF: 0.00652

Gnomad4 AMR exome AF: 0.00906

Gnomad4 ASJ exome AF: 0.00843

Gnomad4 EAS exome AF: 0.000253

Gnomad4 SAS exome AF: 0.0274

Gnomad4 FIN exome AF: 0.0632

Gnomad4 NFE exome AF: 0.0313

Gnomad4 OTH exome AF: 0.0250

GnomAD4 genome AF: 0.0238 AC: 3623 AN: 152362 Hom.: 72 Cov.: 34 AF XY: 0.0253 AC XY: 1888 AN XY: 74504

Gnomad4 AFR AF: 0.00644

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.0734

Gnomad4 NFE AF: 0.0319

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0291 Hom.: 35

Bravo AF: 0.0186

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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 27, 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. -

Jul 21, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myopathy 18 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thyrotoxic periodic paralysis, susceptibility to, 1 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: 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 03, 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

Apr 11, 2023

Genome-Nilou Lab

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	-0.70
CADD	Benign	1.6
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00045
dbscSNV1_RF	Benign	0.032
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: rs79984703; hg19: chr1-201043627;