1-201053283-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000069.3(CACNA1S):c.3796-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,613,782 control chromosomes in the GnomAD database, including 371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 31 hom., cov: 32)

Exomes 𝑓: 0.018 ( 340 hom. )

Consequence

CACNA1S
NM_000069.3 intron

Scores

Splicing: ADA: 0.0001932

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.0130

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):

congenital myopathy
Inheritance: AD, AR, SD Classification: STRONG Submitted by: Genomics England PanelApp, Illumina
congenital myopathy 18
Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
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)
hypokalemic periodic paralysis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA1S links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000069.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 1-201053283-C-T is Benign according to our data. Variant chr1-201053283-C-T is described in ClinVar as Benign. ClinVar VariationId is 254829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0154 (2348/152270) while in subpopulation NFE AF = 0.0231 (1570/67996). AF 95% confidence interval is 0.0221. There are 31 homozygotes in GnomAd4. There are 1200 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 SD,AD,AR 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.3796-9G>A		intron	N/A	NP_000060.2	Q13698

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.3796-9G>A	intron	N/A	ENSP00000355192.3	Q13698
CACNA1S	ENST00000367338.7	TSL:5	c.3739-9G>A	intron	N/A	ENSP00000356307.3	B1ALM3
CACNA1S	ENST00000681874.1		c.3736-9G>A	intron	N/A	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2348

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00311

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0359

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0231

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.0156

AC:

3909

AN:

251184

AF XY:

0.0157

show subpopulations

Gnomad AFR exome

AF:

0.00302

Gnomad AMR exome

AF:

0.00743

Gnomad ASJ exome

AF:

0.00844

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0383

Gnomad NFE exome

AF:

0.0216

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.0182

AC:

26539

AN:

1461512

Hom.:

340

Cov.:

AF XY:

0.0179

AC XY:

13007

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.00251

AC:

AN:

33478

American (AMR)

AF:

0.00760

AC:

340

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00685

AC:

179

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00439

AC:

379

AN:

86254

European-Finnish (FIN)

AF:

0.0374

AC:

1995

AN:

53374

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0203

AC:

22512

AN:

1111690

Other (OTH)

AF:

0.0172

AC:

1036

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

1296

2593

3889

5186

6482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

788

1576

2364

3152

3940

<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:

0.0154

AC:

2348

AN:

152270

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1200

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00310

AC:

129

AN:

41570

American (AMR)

AF:

0.0133

AC:

204

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0359

AC:

381

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0231

AC:

1570

AN:

67996

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

118

236

355

473

591

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0204

Hom.:

Bravo

AF:

0.0120

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Malignant hyperthermia, susceptibility to, 5 (3)

Hypokalemic periodic paralysis, type 1 (2)

Congenital myopathy 18 (1)

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

not provided (1)

Thyrotoxic periodic paralysis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.2

(source)

DANN

Benign

0.74

PhyloP100

0.013

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00019

dbscSNV1_RF

Benign

0.0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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