rs756090938

Variant summary

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

The NM_000069.3(CACNA1S):​c.5574C>T​(p.Leu1858Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,459,464 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: not found (cov: 34)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.74
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]

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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=-0.84).
BP6
Variant 1-201039879-G-A is Benign according to our data. Variant chr1-201039879-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 254851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-1.74 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1SNM_000069.3 linkuse as main transcriptc.5574C>T p.Leu1858Leu synonymous_variant 44/44 ENST00000362061.4 NP_000060.2 Q13698
CACNA1SXM_005245478.4 linkuse as main transcriptc.5517C>T p.Leu1839Leu synonymous_variant 43/43 XP_005245535.1 B1ALM3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1SENST00000362061.4 linkuse as main transcriptc.5574C>T p.Leu1858Leu synonymous_variant 44/441 NM_000069.3 ENSP00000355192.3 Q13698

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
249722
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135132
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 SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000110
AC:
16
AN:
1459464
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
726172
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
Alfa
AF:
0.0000936
Hom.:
0
Bravo
AF:
0.00000378
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 5 Benign:2
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJun 08, 2023This 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 1/249722 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. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
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- -
Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 08, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
CADD
Benign
0.055
DANN
Benign
0.77

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: rs756090938; hg19: chr1-201009007; COSMIC: COSV62943562; COSMIC: COSV62943562; API