1-201083172-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7

The NM_000069.3(CACNA1S):ā€‹c.1383C>Gā€‹(p.Thr461Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,614,122 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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000046 ( 0 hom., cov: 33)
Exomes š‘“: 0.00012 ( 0 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.636
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 1-201083172-G-C is Benign according to our data. Variant chr1-201083172-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 254790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.636 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1SNM_000069.3 linkc.1383C>G p.Thr461Thr synonymous_variant 10/44 ENST00000362061.4 NP_000060.2 Q13698
CACNA1SXM_005245478.4 linkc.1383C>G p.Thr461Thr synonymous_variant 10/43 XP_005245535.1 B1ALM3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1SENST00000362061.4 linkc.1383C>G p.Thr461Thr synonymous_variant 10/441 NM_000069.3 ENSP00000355192.3 Q13698

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00316
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000103
AC:
26
AN:
251250
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135828
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000167
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000119
AC:
174
AN:
1461800
Hom.:
0
Cov.:
31
AF XY:
0.000127
AC XY:
92
AN XY:
727186
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000151
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000115
Gnomad4 OTH exome
AF:
0.000248
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152322
Hom.:
0
Cov.:
33
AF XY:
0.0000268
AC XY:
2
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000203
Hom.:
0
Bravo
AF:
0.0000567
EpiCase
AF:
0.000436
EpiControl
AF:
0.000296

ClinVar

Significance: Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 14, 2022- -
Hypokalemic periodic paralysis, type 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Congenital myopathy 18 Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Thyrotoxic periodic paralysis, susceptibility to, 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024CACNA1S: BP4, BP7 -
Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 03, 2024- -
Malignant hyperthermia, susceptibility to, 5 Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
CADD
Benign
3.4
DANN
Benign
0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144920422; hg19: chr1-201052300; API