rs72749169

Positions:

chr1-201039883-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000362061.4(CACNA1S):c.5570G>A(p.Ser1857Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 1,612,148 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0034 ( 12 hom. )

Consequence

CACNA1S
ENST00000362061.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 3.42

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:

(HGNC:):

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=0.0077617764).

BP6

Variant 1-201039883-C-T is Benign according to our data. Variant chr1-201039883-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 254850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201039883-C-T is described in Lovd as [Benign]. Variant chr1-201039883-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00203 (309/152248) while in subpopulation NFE AF= 0.00368 (250/67988). AF 95% confidence interval is 0.0033. There are 1 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 12 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3 linkuse as main transcript	c.5570G>A	p.Ser1857Asn	missense_variant	44/44	ENST00000362061.4	NP_000060.2
LOC101929305	XR_922410.3 linkuse as main transcript	n.1378-1972C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.5570G>A	p.Ser1857Asn	missense_variant	44/44	1	NM_000069.3	ENSP00000355192	P2
	ENST00000415359.1 linkuse as main transcript	n.211-1972C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

310

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00369

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00211

AC:

528

AN:

250056

Hom.:

AF XY:

0.00217

AC XY:

293

AN XY:

135308

show subpopulations

Gnomad AFR exome

AF:

0.000985

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00117

Gnomad NFE exome

AF:

0.00400

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00341

AC:

4983

AN:

1459900

Hom.:

Cov.:

AF XY:

0.00336

AC XY:

2438

AN XY:

726378

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00128

Gnomad4 NFE exome

AF:

0.00424

Gnomad4 OTH exome

AF:

0.00235

GnomAD4 genome

AF:

0.00203

AC:

309

AN:

152248

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00169

Gnomad4 NFE

AF:

0.00368

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00362

Hom.:

Bravo

AF:

0.00198

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00187

AC:

227

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00456

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	This variant is associated with the following publications: (PMID: 28259615, 30325262, 32859249) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CACNA1S: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2023	- -

Malignant hyperthermia, susceptibility to, 5

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 20, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 24, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 08, 2021

- -

Malignant hyperthermia of anesthesia

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Aug 01, 2016

Found in patient having exome sequencing for an unrelated indication. No known history of Malignant hyperthermia. -

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

- -

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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0086

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.050

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.74

T;T

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.0078

T;T

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

1.8

.;L

MutationTaster

Benign

0.67

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.61

N;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.0050

D;D

Sift4G

Benign

0.36

T;T

Polyphen

0.079

.;B

Vest4

0.058

MVP

0.93

MPC

0.11

ClinPred

0.027

GERP RS

4.5

Varity_R

0.17

gMVP

0.24

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