rs12139527

chr1-201040054-A-Gchr1-201040054-A-T

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.5399T>C(p.Leu1800Ser) variant causes a missense change. The variant allele was found at a frequency of 0.146 in 1,614,082 control chromosomes in the GnomAD database, including 24,387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1800L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (7242 hom., cov: 34)
  • Exomes 𝑓: 0.14 (17145 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.82

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020485818).
• BP6: Variant 1-201040054-A-G is Benign according to our data. Variant chr1-201040054-A-G is described in ClinVar as [Benign]. Clinvar id is 254847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201040054-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1S	NM_000069.3	c.5399T>C	p.Leu1800Ser	missense_variant	44/44	ENST00000362061.4
LOC101929305	XR_922410.3	n.1378-1801A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4	c.5399T>C	p.Leu1800Ser	missense_variant	44/44	1	NM_000069.3	P2
	ENST00000415359.1	n.211-1801A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37109 AN: 152104 Hom.: 7235 Cov.: 34

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0697

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.197

GnomAD3 exomes AF: 0.147 AC: 36827 AN: 250696 Hom.: 4334 AF XY: 0.138 AC XY: 18645 AN XY: 135552

Gnomad AFR exome AF: 0.560

Gnomad AMR exome AF: 0.0878

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.125

Gnomad SAS exome AF: 0.0723

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.136 AC: 199110 AN: 1461860 Hom.: 17145 Cov.: 34 AF XY: 0.133 AC XY: 96807 AN XY: 727234

Gnomad4 AFR exome AF: 0.559

Gnomad4 AMR exome AF: 0.0948

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.0729

Gnomad4 FIN exome AF: 0.139

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.244 AC: 37143 AN: 152222 Hom.: 7242 Cov.: 34 AF XY: 0.238 AC XY: 17750 AN XY: 74446

Gnomad4 AFR AF: 0.543

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.0690

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.194

Alfa AF: 0.145 Hom.: 4076

Bravo AF: 0.261

TwinsUK AF: 0.132 AC: 489

ALSPAC AF: 0.129 AC: 498

ESP6500AA AF: 0.541 AC: 2385

ESP6500EA AF: 0.131 AC: 1124

ExAC AF: 0.155 AC: 18788

Asia WGS AF: 0.118 AC: 409 AN: 3478

EpiCase AF: 0.122

EpiControl AF: 0.126

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 21, 2017	- -

Malignant hyperthermia, susceptibility to, 5 Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
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	Genome-Nilou Lab	Apr 11, 2023	- -

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.48
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.022	T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	0.13	P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.076	T;T
Polyphen		1.0	.;D
Vest4		0.11
MPC		0.62
ClinPred		0.027	T
GERP RS		4.9
Varity_R		0.15
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs12139527; hg19: chr1-201009182; COSMIC: COSV62942385; COSMIC: COSV62942385;