NM_000069.3:c.5238G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

The NM_000069.3(CACNA1S):​c.5238G>A​(p.Val1746Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

2

Clinical Significance

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

Conservation

PhyloP100: -2.08

Publications

0 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 18
    Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • hypokalemic periodic paralysis, type 1
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
  • malignant hyperthermia, susceptibility to, 5
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • congenital myopathy
    Inheritance: SD, AR, AD Classification: STRONG Submitted by: Illumina, Genomics England PanelApp
  • hypokalemic periodic paralysis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 1-201040363-C-T is Benign according to our data. Variant chr1-201040363-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541067.
BP7
Synonymous conserved (PhyloP=-2.08 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1SNM_000069.3 linkc.5238G>A p.Val1746Val synonymous_variant Exon 43 of 44 ENST00000362061.4 NP_000060.2 Q13698
CACNA1SXM_005245478.4 linkc.5181G>A p.Val1727Val synonymous_variant Exon 42 of 43 XP_005245535.1 B1ALM3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1SENST00000362061.4 linkc.5238G>A p.Val1746Val synonymous_variant Exon 43 of 44 1 NM_000069.3 ENSP00000355192.3 Q13698

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000802
AC:
2
AN:
249476
AF XY:
0.00000740
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461080
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
726806
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44684
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86208
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52822
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
0.00000270
AC:
3
AN:
1111914
Other (OTH)
AF:
0.00
AC:
0
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000197
AC:
3
AN:
152224
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74358
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41464
American (AMR)
AF:
0.00
AC:
0
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10632
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 5 Uncertain:1
Jul 10, 2023
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is located in the CACNA1S protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CACNA1S-related disorders in the literature. This variant has been identified in 3/280856 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
Jun 25, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.89
CADD
Benign
0.035
DANN
Benign
0.52
PhyloP100
-2.1
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs374660431; hg19: chr1-201009491; API