rs139956524

chr1-201069522-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000069.3(CACNA1S):c.2440G>A(p.Ala814Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,592,980 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A814P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.32

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024012804).
• BP6: Variant 1-201069522-C-T is Benign according to our data. Variant chr1-201069522-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 294744.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}. Variant chr1-201069522-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00131 (200/152254) while in subpopulation NFE AF= 0.00237 (161/68024). AF 95% confidence interval is 0.00207. There are 0 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1S	NM_000069.3	c.2440G>A	p.Ala814Thr	missense_variant	18/44	ENST00000362061.4
CACNA1S	XM_005245478.4	c.2440G>A	p.Ala814Thr	missense_variant	18/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4	c.2440G>A	p.Ala814Thr	missense_variant	18/44	1	NM_000069.3	P2

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00121 AC: 254 AN: 210546 Hom.: 0 AF XY: 0.00119 AC XY: 134 AN XY: 112358

Gnomad AFR exome AF: 0.000293

Gnomad AMR exome AF: 0.000458

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000310

Gnomad FIN exome AF: 0.000164

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00188

GnomAD4 exome AF: 0.00198 AC: 2846 AN: 1440726 Hom.: 6 Cov.: 31 AF XY: 0.00190 AC XY: 1357 AN XY: 714162

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000580

Gnomad4 ASJ exome AF: 0.00269

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.000219

Gnomad4 FIN exome AF: 0.000134

Gnomad4 NFE exome AF: 0.00236

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00120 AC XY: 89 AN XY: 74432

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00237

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00196 Hom.: 2

Bravo AF: 0.00132

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00100 AC: 120

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2021	This variant is associated with the following publications: (PMID: 25132214, 25735680, 27153395) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

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

-

- -

CACNA1S-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 08, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypokalemic periodic paralysis, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Malignant hyperthermia, susceptibility to, 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.024	T;T
MetaSVM	Uncertain	0.38	D
MutationTaster	Benign	0.60	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.026	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.0080	.;B
Vest4		0.36
MVP		0.90
MPC		0.10
ClinPred		0.045	T
GERP RS		2.7
Varity_R		0.12
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139956524; hg19: chr1-201038650; COSMIC: COSV99054144;