1-201089385-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000069.3(CACNA1S):c.773G>A(p.Gly258Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0103 in 1,614,242 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts 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. G258V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0075 ( 7 hom., cov: 33)

Exomes 𝑓: 0.011 ( 96 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 4.81

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

hypokalemic periodic paralysis, type 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
malignant hyperthermia, susceptibility to, 5
Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
congenital myopathy 18
Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
congenital myopathy
Inheritance: SD, AD, AR Classification: STRONG Submitted by: Illumina, Genomics England PanelApp
hypokalemic periodic paralysis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA1S links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 1-201089385-C-T is Benign according to our data. Variant chr1-201089385-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00749 (1141/152380) while in subpopulation AMR AF = 0.0114 (175/15314). AF 95% confidence interval is 0.0105. There are 7 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000069.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	NM_000069.3	MANE Select	c.773G>A	p.Gly258Asp	missense	Exon 6 of 44	NP_000060.2	Q13698

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.773G>A	p.Gly258Asp	missense	Exon 6 of 44	ENSP00000355192.3	Q13698
CACNA1S	ENST00000367338.7	TSL:5	c.773G>A	p.Gly258Asp	missense	Exon 6 of 43	ENSP00000356307.3	B1ALM3
CACNA1S	ENST00000681874.1		c.773G>A	p.Gly258Asp	missense	Exon 6 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes

AF:

0.00749

AC:

1141

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.00789

AC:

1982

AN:

251222

AF XY:

0.00816

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00633

Gnomad ASJ exome

AF:

0.0192

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00194

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.0106

AC:

15496

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

7722

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00167

AC:

AN:

33480

American (AMR)

AF:

0.00680

AC:

304

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0174

AC:

454

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00416

AC:

359

AN:

86254

European-Finnish (FIN)

AF:

0.00215

AC:

115

AN:

53406

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0121

AC:

13504

AN:

1112004

Other (OTH)

AF:

0.0114

AC:

686

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1009

2019

3028

4038

5047

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

498

996

1494

1992

2490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00749

AC:

1141

AN:

152380

Hom.:

Cov.:

AF XY:

0.00717

AC XY:

534

AN XY:

74524

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

41586

American (AMR)

AF:

0.0114

AC:

175

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00310

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00254

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0111

AC:

757

AN:

68036

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

126

189

252

315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00990

Hom.:

Bravo

AF:

0.00802

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0110

AC:

ExAC

AF:

0.00739

AC:

897

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0119

EpiControl

AF:

0.0116

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (3)

Hypokalemic periodic paralysis, type 1 (2)

Malignant hyperthermia, susceptibility to, 5 (2)

Congenital myopathy 18 (1)

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

Thyrotoxic periodic paralysis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.83

MetaRNN

Benign

0.016

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

1.9

PhyloP100

4.8

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.1

REVEL

Pathogenic

0.78

Sift

Benign

0.096

Sift4G

Benign

0.085

Polyphen

0.99

Vest4

0.89

MVP

0.97

MPC

0.27

ClinPred

0.031

GERP RS

4.8

Varity_R

0.65

gMVP

0.90

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over