Variant chr1-201077947-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000069.3(CACNA1S):c.1551T>C(p.Gly517=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 1,613,174 control chromosomes in the GnomAD database, including 337,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 37788 hom., cov: 33)

Exomes 𝑓: 0.63 ( 299855 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.15

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 1-201077947-A-G is Benign according to our data. Variant chr1-201077947-A-G is described in ClinVar as [Benign]. Clinvar id is 254800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201077947-A-G is described in Lovd as [Pathogenic]. Variant chr1-201077947-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.15 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.885 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.1551T>C	p.Gly517=	synonymous_variant	11/44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4 linkuse as main transcript	c.1551T>C	p.Gly517=	synonymous_variant	11/43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.1551T>C	p.Gly517=	synonymous_variant	11/44	1	NM_000069.3	ENSP00000355192	P2

Frequencies

GnomAD3 genomes

AF:

0.685

AC:

104086

AN:

152006

Hom.:

37747

Cov.:

show subpopulations

Gnomad AFR

AF:

0.893

Gnomad AMI

AF:

0.689

Gnomad AMR

AF:

0.652

Gnomad ASJ

AF:

0.712

Gnomad EAS

AF:

0.234

Gnomad SAS

AF:

0.295

Gnomad FIN

AF:

0.522

Gnomad MID

AF:

0.728

Gnomad NFE

AF:

0.651

Gnomad OTH

AF:

0.690

GnomAD3 exomes

AF:

0.579

AC:

145567

AN:

251274

Hom.:

45757

AF XY:

0.567

AC XY:

76949

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.896

Gnomad AMR exome

AF:

0.586

Gnomad ASJ exome

AF:

0.706

Gnomad EAS exome

AF:

0.225

Gnomad SAS exome

AF:

0.321

Gnomad FIN exome

AF:

0.534

Gnomad NFE exome

AF:

0.654

Gnomad OTH exome

AF:

0.611

GnomAD4 exome

AF:

0.630

AC:

919893

AN:

1461050

Hom.:

299855

Cov.:

AF XY:

0.620

AC XY:

450324

AN XY:

726856

show subpopulations

Gnomad4 AFR exome

AF:

0.903

Gnomad4 AMR exome

AF:

0.590

Gnomad4 ASJ exome

AF:

0.712

Gnomad4 EAS exome

AF:

0.256

Gnomad4 SAS exome

AF:

0.321

Gnomad4 FIN exome

AF:

0.545

Gnomad4 NFE exome

AF:

0.663

Gnomad4 OTH exome

AF:

0.624

GnomAD4 genome

AF:

0.685

AC:

104183

AN:

152124

Hom.:

37788

Cov.:

AF XY:

0.668

AC XY:

49693

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.893

Gnomad4 AMR

AF:

0.651

Gnomad4 ASJ

AF:

0.712

Gnomad4 EAS

AF:

0.234

Gnomad4 SAS

AF:

0.295

Gnomad4 FIN

AF:

0.522

Gnomad4 NFE

AF:

0.651

Gnomad4 OTH

AF:

0.689

Alfa

AF:

0.674

Hom.:

42849

Bravo

AF:

0.710

Asia WGS

AF:

0.302

AC:

1057

AN:

3478

EpiCase

AF:

0.661

EpiControl

AF:

0.677

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 11940049) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 11, 2016	Variant summary: c.1551T>C affects a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts this variant to be benign. 4/5 in silico tools via Alamut predict no change on RNA splicing site and ESEfinder predicts a gain of binding motif for splicing enhancer. This variant was found in 70806/121258 control chromosomes (with 22620 homozygotes) from ExAC at a frequency of 0.5839285, which significantly exceeds the maximal expected frequency of a pathogenic allele (0.0000013), suggesting this variant is a benign polymorphism. Taken together, considering the high frequency in controls and lack of predicted effect on splicing, this variant was classified as Benign. -

Hypokalemic periodic paralysis, type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Malignant hyperthermia, susceptibility to, 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.90

DANN

Benign

0.60

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