NM_000069.3:c.2467C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000069.3(CACNA1S):c.2467C>T(p.Arg823Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000412 in 1,602,138 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R823Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 3.75

Publications

2 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: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 1-201069495-G-A is Benign according to our data. Variant chr1-201069495-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 473977.

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.2467C>T	p.Arg823Trp	missense	Exon 18 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.2467C>T	p.Arg823Trp	missense	Exon 18 of 44	ENSP00000355192.3	Q13698
CACNA1S	ENST00000367338.7	TSL:5	c.2467C>T	p.Arg823Trp	missense	Exon 18 of 43	ENSP00000356307.3	B1ALM3
CACNA1S	ENST00000681874.1		c.2467C>T	p.Arg823Trp	missense	Exon 18 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000665

AC:

AN:

225458

AF XY:

0.0000744

show subpopulations

Gnomad AFR exome

AF:

0.000137

Gnomad AMR exome

AF:

0.0000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000121

Gnomad FIN exome

AF:

0.0000515

Gnomad NFE exome

AF:

0.0000493

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000372

AC:

AN:

1449852

Hom.:

Cov.:

AF XY:

0.0000375

AC XY:

AN XY:

719556

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33454

American (AMR)

AF:

0.0000236

AC:

AN:

42368

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25740

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39266

South Asian (SAS)

AF:

0.0000843

AC:

AN:

83078

European-Finnish (FIN)

AF:

0.000114

AC:

AN:

52564

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000289

AC:

AN:

1107610

Other (OTH)

AF:

0.0000500

AC:

AN:

60024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000788

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41544

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000879

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000748

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Malignant hyperthermia, susceptibility to, 5 (1)

Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1 (1)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.58

MetaSVM

Pathogenic

0.82

MutationAssessor

Uncertain

2.0

PhyloP100

3.7

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.61

Sift

Uncertain

0.015

Sift4G

Benign

0.11

Polyphen

0.99

Vest4

0.49

MVP

0.96

MPC

0.41

ClinPred

0.84

GERP RS

3.7

Varity_R

0.47

gMVP

0.75

Mutation Taster

=86/14

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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