1-201050977-A-G

Variant names:

• chr1-201050977-A-G
• rs6702590
• NM_000069.3:c.4113+7T>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.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
• Publications: 18 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=-0.86).
• BP6: Variant 1-201050977-A-G is Benign according to our data. Variant chr1-201050977-A-G is described in ClinVar as Benign. ClinVar VariationId is 199680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 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

GnomAD2 exomes AF: 0.775 AC: 194789 AN: 251432 AF XY: 0.769

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 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

African (AFR) AF: 0.941 AC: 31489 AN: 33480

American (AMR) AF: 0.865 AC: 38677 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 19407 AN: 26126

East Asian (EAS) AF: 0.983 AC: 39038 AN: 39696

South Asian (SAS) AF: 0.867 AC: 74770 AN: 86252

European-Finnish (FIN) AF: 0.758 AC: 40486 AN: 53420

Middle Eastern (MID) AF: 0.773 AC: 4448 AN: 5752

European-Non Finnish (NFE) AF: 0.658 AC: 731550 AN: 1111488

Other (OTH) AF: 0.733 AC: 44261 AN: 60378

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

African (AFR) AF: 0.929 AC: 38564 AN: 41520

American (AMR) AF: 0.802 AC: 12273 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 2581 AN: 3470

East Asian (EAS) AF: 0.994 AC: 5125 AN: 5156

South Asian (SAS) AF: 0.875 AC: 4223 AN: 4824

European-Finnish (FIN) AF: 0.770 AC: 8156 AN: 10596

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.666 AC: 45256 AN: 67974

Other (OTH) AF: 0.777 AC: 1641 AN: 2112

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

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

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6702590; hg19: chr1-201020105;