rs34515088

Positions:

• chr1-201060811-T-C
• chr1-201060811-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000069.3(CACNA1S):​c.3261A>G​(p.Gln1087=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,614,142 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (18 hom., cov: 33)
  • Exomes 𝑓: 0.013 (157 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.07

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-201060811-T-C is Benign according to our data. Variant chr1-201060811-T-C is described in ClinVar as [Benign]. Clinvar id is 254825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201060811-T-C is described in Lovd as [Benign]. Variant chr1-201060811-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0097 (1478/152298) while in subpopulation AMR AF= 0.016 (245/15296). AF 95% confidence interval is 0.0144. There are 18 homozygotes in gnomad4. There are 714 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.3261A>G	p.Gln1087=	synonymous_variant	26/44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.3261A>G	p.Gln1087=	synonymous_variant	26/43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.3261A>G	p.Gln1087=	synonymous_variant	26/44	1	NM_000069.3	ENSP00000355192	P2

Frequencies

GnomAD3 genomes AF: 0.00971 AC: 1478 AN: 152180 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00883 AC: 2221 AN: 251470 Hom.: 16 AF XY: 0.00906 AC XY: 1232 AN XY: 135914

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00726

Gnomad ASJ exome AF: 0.00982

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.00425

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0126 AC: 18384 AN: 1461844 Hom.: 157 Cov.: 32 AF XY: 0.0124 AC XY: 9008 AN XY: 727224

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00754

Gnomad4 ASJ exome AF: 0.00999

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00264

Gnomad4 FIN exome AF: 0.00532

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.00970 AC: 1478 AN: 152298 Hom.: 18 Cov.: 33 AF XY: 0.00959 AC XY: 714 AN XY: 74480

Gnomad4 AFR AF: 0.00269

Gnomad4 AMR AF: 0.0160

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00414

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0110 Hom.: 7

Bravo AF: 0.00992

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0160

EpiControl AF: 0.0160

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CACNA1S: BP4, BP7, BS1, BS2 -

Malignant hyperthermia, susceptibility to, 5 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 17, 2022	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2016	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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Congenital myopathy 18 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Thyrotoxic periodic paralysis, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs34515088; hg19: chr1-201029939;