rs1131691712
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1PM2_SupportingPP5_Very_Strong
The NM_001127222.2(CACNA1A):c.3103_3104insT(p.Ser1035PhefsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S1035S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Consequence
CACNA1A
NM_001127222.2 frameshift
NM_001127222.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.323
Links
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 31.
PP5
?
Variant 19-13286952-G-GA is Pathogenic according to our data. Variant chr19-13286952-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 429987. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.3103_3104insT | p.Ser1035PhefsTer32 | frameshift_variant | 20/47 | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.3103_3104insT | p.Ser1035PhefsTer32 | frameshift_variant | 20/47 | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomesCov.: 31
GnomAD3 genomes
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 28, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2017 | The c.3106dupT variant in the CACNA1A gene has not been reported previously as a pathogenicvariant nor as a benign variant, to our knowledge. The c.3106dupT variant causes a frameshift startingwith codon Serine 1036, changes this amino acid to a Phenylalanine residue, and creates a prematureStop codon at position 32 of the new reading frame, denoted p.Ser1036PhefsX32. This variant ispredicted to cause loss of normal protein function either through protein truncation or nonsensemediatedmRNA decay. The c.3106dupT variant is not observed in large population cohorts (Lek etal., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.3106dupTas a pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at