1-201050977-A-G

Variant names:

• chr1-201050977-A-G
• rs6702590
• NM_000069.3:c.4113+7T>C

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.4113+7T>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 0.708 in 1,613,468 control chromosomes in the GnomAD database, including 412,372 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 0.78 (47269 hom., cov: 31)
  • Exomes 𝑓: 0.70 (365103 hom.)
• Consequence: CACNA1S NM_000069.3 splice_region, intron
• Scores: Splicing: ADA: 0.000007173
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.150

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=-0.86).
• BP6: Variant 1-201050977-A-G is Benign according to our data. Variant chr1-201050977-A-G is described in ClinVar as [Benign]. Clinvar id is 199680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201050977-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.4113+7T>C		splice_region_variant, intron_variant	Intron 33 of 43	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.4056+7T>C		splice_region_variant, intron_variant	Intron 32 of 42		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.4113+7T>C		splice_region_variant, intron_variant	Intron 33 of 43	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes AF: 0.779 AC: 118370 AN: 152036 Hom.: 47206 Cov.: 31

Gnomad AFR AF: 0.929

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.744

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.876

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.666

Gnomad OTH AF: 0.775

GnomAD3 exomes AF: 0.775 AC: 194789 AN: 251432 Hom.: 77324 AF XY: 0.769 AC XY: 104568 AN XY: 135904

Gnomad AFR exome AF: 0.937

Gnomad AMR exome AF: 0.868

Gnomad ASJ exome AF: 0.745

Gnomad EAS exome AF: 0.996

Gnomad SAS exome AF: 0.866

Gnomad FIN exome AF: 0.762

Gnomad NFE exome AF: 0.669

Gnomad OTH exome AF: 0.756

GnomAD4 exome AF: 0.701 AC: 1024126 AN: 1461314 Hom.: 365103 Cov.: 45 AF XY: 0.705 AC XY: 512320 AN XY: 726970

Gnomad4 AFR exome AF: 0.941

Gnomad4 AMR exome AF: 0.865

Gnomad4 ASJ exome AF: 0.743

Gnomad4 EAS exome AF: 0.983

Gnomad4 SAS exome AF: 0.867

Gnomad4 FIN exome AF: 0.758

Gnomad4 NFE exome AF: 0.658

Gnomad4 OTH exome AF: 0.733

GnomAD4 genome AF: 0.779 AC: 118493 AN: 152154 Hom.: 47269 Cov.: 31 AF XY: 0.786 AC XY: 58431 AN XY: 74338

Gnomad4 AFR AF: 0.929

Gnomad4 AMR AF: 0.802

Gnomad4 ASJ AF: 0.744

Gnomad4 EAS AF: 0.994

Gnomad4 SAS AF: 0.875

Gnomad4 FIN AF: 0.770

Gnomad4 NFE AF: 0.666

Gnomad4 OTH AF: 0.777

Alfa AF: 0.719 Hom.: 17212

Bravo AF: 0.790

Asia WGS AF: 0.928 AC: 3226 AN: 3478

EpiCase AF: 0.683

EpiControl AF: 0.670

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

- -

Jul 21, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

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.4113+7T>C variant affects a non-conserved nucleotide, resulting in intronic change. 5/5 in silico tools via Alamut predict this variant not to affect normal splicing. This variant was found in 93542/121404 control chromosomes from ExAC at a frequency of 0.7705018, which is more than 616400 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. One lab (via ClinVar) has classified this variant as benign. Taken together, this variant has been classified as Benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.18
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000072
dbscSNV1_RF	Benign	0.0
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: rs6702590; hg19: chr1-201020105;