chr1-201075485-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_000069.3(CACNA1S):​c.1948+10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,509,420 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0012 ( 0 hom. )

Consequence

CACNA1S
NM_000069.3 intron

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.55

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: Benign. The variant received -16 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BP6
Variant 1-201075485-G-C is Benign according to our data. Variant chr1-201075485-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 254805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201075485-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 254805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201075485-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 254805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201075485-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 254805.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 = 0.00096 (131/136438) while in subpopulation NFE AF = 0.000975 (64/65636). AF 95% confidence interval is 0.000783. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1SNM_000069.3 linkc.1948+10C>G intron_variant Intron 13 of 43 ENST00000362061.4 NP_000060.2 Q13698
CACNA1SXM_005245478.4 linkc.1948+10C>G intron_variant Intron 13 of 42 XP_005245535.1 B1ALM3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1SENST00000362061.4 linkc.1948+10C>G intron_variant Intron 13 of 43 1 NM_000069.3 ENSP00000355192.3 Q13698

Frequencies

GnomAD3 genomes
AF:
0.000960
AC:
131
AN:
136394
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.000484
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000499
Gnomad ASJ
AF:
0.00118
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00431
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000975
Gnomad OTH
AF:
0.00270
GnomAD2 exomes
AF:
0.000570
AC:
143
AN:
250964
AF XY:
0.000538
show subpopulations
Gnomad AFR exome
AF:
0.000369
Gnomad AMR exome
AF:
0.000290
Gnomad ASJ exome
AF:
0.000596
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00131
Gnomad NFE exome
AF:
0.000783
Gnomad OTH exome
AF:
0.000653
GnomAD4 exome
AF:
0.00117
AC:
1605
AN:
1372982
Hom.:
0
Cov.:
39
AF XY:
0.00111
AC XY:
761
AN XY:
683276
show subpopulations
African (AFR)
AF:
0.000289
AC:
9
AN:
31168
American (AMR)
AF:
0.000303
AC:
13
AN:
42902
Ashkenazi Jewish (ASJ)
AF:
0.000630
AC:
15
AN:
23806
East Asian (EAS)
AF:
0.0000847
AC:
3
AN:
35408
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84414
European-Finnish (FIN)
AF:
0.00127
AC:
61
AN:
48178
Middle Eastern (MID)
AF:
0.000186
AC:
1
AN:
5382
European-Non Finnish (NFE)
AF:
0.00138
AC:
1445
AN:
1046118
Other (OTH)
AF:
0.00104
AC:
58
AN:
55606
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.474
Heterozygous variant carriers
0
78
157
235
314
392
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
56
112
168
224
280
<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:
0.000960
AC:
131
AN:
136438
Hom.:
0
Cov.:
30
AF XY:
0.00110
AC XY:
72
AN XY:
65230
show subpopulations
African (AFR)
AF:
0.000483
AC:
17
AN:
35174
American (AMR)
AF:
0.000499
AC:
6
AN:
12034
Ashkenazi Jewish (ASJ)
AF:
0.00118
AC:
4
AN:
3404
East Asian (EAS)
AF:
0.00
AC:
0
AN:
4658
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4394
European-Finnish (FIN)
AF:
0.00431
AC:
35
AN:
8130
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
256
European-Non Finnish (NFE)
AF:
0.000975
AC:
64
AN:
65636
Other (OTH)
AF:
0.00268
AC:
5
AN:
1868
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.522
Heterozygous variant carriers
0
5
10
16
21
26
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:
0.000171
Hom.:
0

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
-
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 27, 2020
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hypokalemic periodic paralysis, type 1 Benign:2
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Apr 11, 2023
Genome-Nilou Lab
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
Oct 21, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Congenital myopathy 18 Benign:1
Apr 11, 2023
Genome-Nilou Lab
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Thyrotoxic periodic paralysis, susceptibility to, 1 Benign:1
Apr 11, 2023
Genome-Nilou Lab
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 5 Benign:1
Apr 11, 2023
Genome-Nilou Lab
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
-0.92
CADD
Benign
0.028
DANN
Benign
0.37
PhyloP100
-2.6
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs201173419; hg19: chr1-201044613; API