19-13298878-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_001127222.2(CACNA1A):c.2755G>A(p.Glu919Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E919E) has been classified as Likely benign.
Frequency
Consequence
NM_001127222.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.2755G>A | p.Glu919Lys | missense_variant | Exon 19 of 47 | 1 | NM_001127222.2 | ENSP00000353362.5 | ||
CACNA1A | ENST00000638029.1 | c.2767G>A | p.Glu923Lys | missense_variant | Exon 19 of 48 | 5 | ENSP00000489829.1 | |||
CACNA1A | ENST00000573710.7 | c.2761G>A | p.Glu921Lys | missense_variant | Exon 19 of 47 | 5 | ENSP00000460092.3 | |||
CACNA1A | ENST00000635727.1 | c.2758G>A | p.Glu920Lys | missense_variant | Exon 19 of 47 | 5 | ENSP00000490001.1 | |||
CACNA1A | ENST00000637769.1 | c.2758G>A | p.Glu920Lys | missense_variant | Exon 19 of 47 | 1 | ENSP00000489778.1 | |||
CACNA1A | ENST00000636012.1 | c.2758G>A | p.Glu920Lys | missense_variant | Exon 19 of 46 | 5 | ENSP00000490223.1 | |||
CACNA1A | ENST00000637736.1 | c.2617G>A | p.Glu873Lys | missense_variant | Exon 18 of 46 | 5 | ENSP00000489861.1 | |||
CACNA1A | ENST00000636389.1 | c.2758G>A | p.Glu920Lys | missense_variant | Exon 19 of 47 | 5 | ENSP00000489992.1 | |||
CACNA1A | ENST00000637432.1 | c.2767G>A | p.Glu923Lys | missense_variant | Exon 19 of 48 | 5 | ENSP00000490617.1 | |||
CACNA1A | ENST00000636549.1 | c.2758G>A | p.Glu920Lys | missense_variant | Exon 19 of 48 | 5 | ENSP00000490578.1 | |||
CACNA1A | ENST00000637927.1 | c.2761G>A | p.Glu921Lys | missense_variant | Exon 19 of 47 | 5 | ENSP00000489715.1 | |||
CACNA1A | ENST00000635895.1 | c.2758G>A | p.Glu920Lys | missense_variant | Exon 19 of 47 | 5 | ENSP00000490323.1 | |||
CACNA1A | ENST00000638009.2 | c.2758G>A | p.Glu920Lys | missense_variant | Exon 19 of 47 | 1 | ENSP00000489913.1 | |||
CACNA1A | ENST00000637276.1 | c.2758G>A | p.Glu920Lys | missense_variant | Exon 19 of 46 | 5 | ENSP00000489777.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1440972Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 717054
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1
This sequence change replaces glutamic acid with lysine at codon 920 of the CACNA1A protein (p.Glu920Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CACNA1A-related disease. This variant is not present in population databases (ExAC no frequency). -
not provided Uncertain:1
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at