rs145910245

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000069.3(CACNA1S):c.4060A>T(p.Thr1354Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,614,210 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. T1354I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0050 ( 33 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 3.14

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009345293).

BP6

Variant 1-201051037-T-A is Benign according to our data. Variant chr1-201051037-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161208.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3, Benign=1}. Variant chr1-201051037-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00335 (511/152342) while in subpopulation NFE AF= 0.00519 (353/68026). AF 95% confidence interval is 0.00474. There are 1 homozygotes in gnomad4. There are 241 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 33 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3 linkuse as main transcript	c.4060A>T	p.Thr1354Ser	missense_variant	33/44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 linkuse as main transcript	c.4003A>T	p.Thr1335Ser	missense_variant	32/43		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.4060A>T	p.Thr1354Ser	missense_variant	33/44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.00336

AC:

511

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00519

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00264

AC:

663

AN:

251492

Hom.:

AF XY:

0.00260

AC XY:

353

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.00506

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.00438

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00499

AC:

7295

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00473

AC XY:

3441

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.00551

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00191

Gnomad4 NFE exome

AF:

0.00598

Gnomad4 OTH exome

AF:

0.00492

GnomAD4 genome

AF:

0.00335

AC:

511

AN:

152342

Hom.:

Cov.:

AF XY:

0.00323

AC XY:

241

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00115

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00519

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00342

Hom.:

Bravo

AF:

0.00322

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00236

AC:

287

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00480

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 07, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2021	This variant is associated with the following publications: (PMID: 32222817, 29193480, 29212769, 27153395, 27181684, 28011884, 20861472, 24784157, 24055113, 25735680, 25637381, 24195946, 26332594, 27147545) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CACNA1S: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 2016	Variant summary: The CACNA1S c.4060A>T (p.Thr1354Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 287/121696 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0037758 (252/66740). This frequency is about 604 times the estimated maximal expected allele frequency of a pathogenic CACNA1S variant (0.0000063), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant was initially considered pathogenic based on a publication showing segregation of the variant in an affected family, absence in 268 control chromosomes, and functional data demonstrating abnormal Ca++ flux (Pirone_2010). Based on this evidence, Lawrence_2013 listed the variant of interest as a reportable incidental finding in exome sequencing cases. However, the high frequency of this variant in the general population puts into question the true pathogenicity of the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a VUS until additional evidence becomes available. -

Malignant hyperthermia, susceptibility to, 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Oct 30, 2020	This sequence change is predicted to replace threonine with serine at codon 1354 of the CACNA1S protein (p.(Thr1354Ser)). The threonine residue is conserved to fish species, which also have a serine residue at codon 1354 (100 vertebrates, UCSC). The variant is located in the extracellular portion of an ion transporter domain. There is a small physicochemical difference between threonine and serine. The variant is present in a large population cohort at a frequency of 0.52% in the European (non-Finnish) population (rs1145910245, gnomAD v3.0). This variant has been reported in a multigenerational family of individuals who were malignant hyperthermia susceptible (PMID: 20861472) and in two unrelated individuals in an Australian cohort, one of which also had a variant in RYR1 (PMID: 25735680). Patch-clamp analyses demonstrate accelerated inward Ca2+ current and increased sensitisation of RYR1 under caffeine exposure in a transfection model. Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predicting benign/neutral effect, 2/6 algorithms predicting deleterious effect). Based on the classification guidelines RMH Modified ACMG Guidelines v1.3.0, this variant is classified as BENIGN. The following criteria are met: BA1, PP1_Moderate. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 20, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.4% (252/66740) Europeans. Classified as VUS in 3 papers (7 total papers in HGMD) -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

CACNA1S-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2023

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). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Benign

0.33

DEOGEN2

Benign

0.28

T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.83

T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.0093

T;T

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

-1.3

.;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

1.6

N;N

REVEL

Uncertain

0.57

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.090

.;B

Vest4

0.28

MutPred

0.57

.;Gain of disorder (P = 0.086);

MVP

0.87

MPC

0.093

ClinPred

0.034

GERP RS

4.4

Varity_R

0.22

gMVP

0.58

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