1-201043356-C-T

Position:

chr1-201043356-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000069.3(CACNA1S):c.4973G>A(p.Arg1658His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.058 in 1,613,994 control chromosomes in the GnomAD database, including 4,663 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1658C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.11 ( 1603 hom., cov: 32)

Exomes 𝑓: 0.053 ( 3060 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.253

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]

CACNA1S links:

CACNA1S (HGNC:):

CACNA1S links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019210279).

BP6

Variant 1-201043356-C-T is Benign according to our data. Variant chr1-201043356-C-T is described in ClinVar as [Benign]. Clinvar id is 254842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201043356-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3 linkuse as main transcript	c.4973G>A	p.Arg1658His	missense_variant	40/44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 linkuse as main transcript	c.4916G>A	p.Arg1639His	missense_variant	39/43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.4973G>A	p.Arg1658His	missense_variant	40/44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16326

AN:

152024

Hom.:

1596

Cov.:

show subpopulations

Gnomad AFR

AF:

0.261

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0485

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0321

Gnomad FIN

AF:

0.0577

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.0502

Gnomad OTH

AF:

0.0814

GnomAD3 exomes

AF:

0.0613

AC:

15403

AN:

251446

Hom.:

921

AF XY:

0.0577

AC XY:

7835

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.271

Gnomad AMR exome

AF:

0.0342

Gnomad ASJ exome

AF:

0.103

Gnomad EAS exome

AF:

0.000762

Gnomad SAS exome

AF:

0.0376

Gnomad FIN exome

AF:

0.0574

Gnomad NFE exome

AF:

0.0525

Gnomad OTH exome

AF:

0.0637

GnomAD4 exome

AF:

0.0528

AC:

77180

AN:

1461852

Hom.:

3060

Cov.:

AF XY:

0.0516

AC XY:

37498

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.268

Gnomad4 AMR exome

AF:

0.0375

Gnomad4 ASJ exome

AF:

0.100

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0371

Gnomad4 FIN exome

AF:

0.0563

Gnomad4 NFE exome

AF:

0.0478

Gnomad4 OTH exome

AF:

0.0656

GnomAD4 genome

AF:

0.107

AC:

16351

AN:

152142

Hom.:

1603

Cov.:

AF XY:

0.106

AC XY:

7861

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.261

Gnomad4 AMR

AF:

0.0485

Gnomad4 ASJ

AF:

0.101

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0323

Gnomad4 FIN

AF:

0.0577

Gnomad4 NFE

AF:

0.0502

Gnomad4 OTH

AF:

0.0806

Alfa

AF:

0.0624

Hom.:

860

Bravo

AF:

0.114

TwinsUK

AF:

0.0464

AC:

172

ALSPAC

AF:

0.0532

AC:

205

ESP6500AA

AF:

0.253

AC:

1116

ESP6500EA

AF:

0.0530

AC:

456

ExAC

AF:

0.0656

AC:

7965

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0517

EpiControl

AF:

0.0508

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 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	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	Mar 05, 2018	- -

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0073

T;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

2.0

.;M

PrimateAI

Benign

0.33

PROVEAN

Benign

1.3

N;N

REVEL

Benign

0.24

Sift

Benign

0.31

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0

.;B

Vest4

0.043

MPC

0.13

ClinPred

0.031

GERP RS

1.6

Varity_R

0.090

gMVP

0.50

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over