rs140662085

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000069.3(CACNA1S):c.1547C>T(p.Ser516Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,614,134 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S516W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 8 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.894

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009200394).

BP6

Variant 1-201077951-G-A is Benign according to our data. Variant chr1-201077951-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 225281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1S	NM_000069.3 linkuse as main transcript	c.1547C>T	p.Ser516Leu	missense_variant	11/44	ENST00000362061.4
CACNA1S	XM_005245478.4 linkuse as main transcript	c.1547C>T	p.Ser516Leu	missense_variant	11/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.1547C>T	p.Ser516Leu	missense_variant	11/44	1	NM_000069.3	P2

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

215

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0110

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00191

AC:

480

AN:

251440

Hom.:

AF XY:

0.00180

AC XY:

244

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0111

Gnomad NFE exome

AF:

0.00157

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00135

AC:

1980

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

929

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000917

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.0110

Gnomad4 NFE exome

AF:

0.00113

Gnomad4 OTH exome

AF:

0.00134

GnomAD4 genome

AF:

0.00141

AC:

215

AN:

152332

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

125

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0110

Gnomad4 NFE

AF:

0.00129

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00100

Hom.:

Bravo

AF:

0.000729

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00181

AC:

220

EpiCase

AF:

0.00115

EpiControl

AF:

0.00101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Malignant hyperthermia, susceptibility to, 5

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 20, 2022	- -

CACNA1S-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2023

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

Malignant hyperthermia of anesthesia

Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Dec 01, 2015

- -

Congenital myopathy 18

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Thyrotoxic periodic paralysis, susceptibility to, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 21, 2020

This variant is associated with the following publications: (PMID: 26994242, 28326467, 28259615) -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.50

T;T

MetaRNN

Benign

0.0092

T;T

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

0.12

.;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

0.37

N;N

REVEL

Benign

0.28

Sift

Benign

0.83

T;T

Sift4G

Benign

0.69

T;T

Polyphen

0.011

.;B

Vest4

0.15

MVP

0.78

MPC

0.097

ClinPred

0.016

GERP RS

2.6

Varity_R

0.041

gMVP

0.17

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