NM_000069.3:c.4114-8T>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.4114-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000069.3 splice_region, intron
Scores
Clinical Significance
Conservation
Publications
- congenital myopathy 18Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- hypokalemic periodic paralysis, type 1Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
- malignant hyperthermia, susceptibility to, 5Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
- congenital myopathyInheritance: SD, AR, AD Classification: STRONG Submitted by: Illumina, Genomics England PanelApp
- hypokalemic periodic paralysisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1S | NM_000069.3 | c.4114-8T>C | splice_region_variant, intron_variant | Intron 33 of 43 | ENST00000362061.4 | NP_000060.2 | ||
CACNA1S | XM_005245478.4 | c.4057-8T>C | splice_region_variant, intron_variant | Intron 32 of 42 | XP_005245535.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000723 AC: 110AN: 152154Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000565 AC: 142AN: 251430 AF XY: 0.000589 show subpopulations
GnomAD4 exome AF: 0.00111 AC: 1628AN: 1461750Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 796AN XY: 727180 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000723 AC: 110AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.000686 AC XY: 51AN XY: 74314 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Benign:3
CACNA1S: BP4 -
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Hypokalemic periodic paralysis, type 1 Benign:2
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. -
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Malignant hyperthermia, susceptibility to, 5 Benign:2
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not specified Benign:1
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Congenital myopathy 18 Benign:1
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Thyrotoxic periodic paralysis, susceptibility to, 1 Benign:1
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Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at