chr1-201039955-AGTAGCTCT-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBS1BS2

The NM_000069.3(CACNA1S):​c.5490_5497delAGAGCTAC​(p.Leu1832ArgfsTer67) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,614,182 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 10 hom., cov: 34)
Exomes 𝑓: 0.00055 ( 5 hom. )

Consequence

CACNA1S
NM_000069.3 frameshift

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.60
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0235 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
BP6
Variant 1-201039955-AGTAGCTCT-A is Benign according to our data. Variant chr1-201039955-AGTAGCTCT-A is described in ClinVar as [Likely_benign]. Clinvar id is 254849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00561 (855/152314) while in subpopulation AFR AF= 0.0197 (817/41570). AF 95% confidence interval is 0.0185. There are 10 homozygotes in gnomad4. There are 398 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 10 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1SNM_000069.3 linkc.5490_5497delAGAGCTAC p.Leu1832ArgfsTer67 frameshift_variant Exon 44 of 44 ENST00000362061.4 NP_000060.2 Q13698
CACNA1SXM_005245478.4 linkc.5433_5440delAGAGCTAC p.Leu1813ArgfsTer67 frameshift_variant Exon 43 of 43 XP_005245535.1 B1ALM3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1SENST00000362061.4 linkc.5490_5497delAGAGCTAC p.Leu1832ArgfsTer67 frameshift_variant Exon 44 of 44 1 NM_000069.3 ENSP00000355192.3 Q13698

Frequencies

GnomAD3 genomes
AF:
0.00557
AC:
848
AN:
152196
Hom.:
10
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0195
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00203
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00126
AC:
316
AN:
251410
Hom.:
2
AF XY:
0.000949
AC XY:
129
AN XY:
135878
show subpopulations
Gnomad AFR exome
AF:
0.0179
Gnomad AMR exome
AF:
0.000405
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000616
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000545
AC:
797
AN:
1461868
Hom.:
5
AF XY:
0.000484
AC XY:
352
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.0193
Gnomad4 AMR exome
AF:
0.000559
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000288
Gnomad4 OTH exome
AF:
0.00136
GnomAD4 genome
AF:
0.00561
AC:
855
AN:
152314
Hom.:
10
Cov.:
34
AF XY:
0.00534
AC XY:
398
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.0197
Gnomad4 AMR
AF:
0.00196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00295
Hom.:
0
Bravo
AF:
0.00595
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.000273
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
May 26, 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. -

-
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 30, 2019
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypokalemic periodic paralysis, type 1 Benign:1
Apr 11, 2023
Genome-Nilou Lab
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Congenital myopathy 18 Benign:1
Apr 11, 2023
Genome-Nilou Lab
Significance: Likely 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: 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 02, 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: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs554596425; hg19: chr1-201009083; API