rs747083495
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP2PP3BP6
The NM_000719.7(CACNA1C):c.50G>A(p.Gly17Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,404,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000719.7 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.50G>A | p.Gly17Asp | missense_variant, splice_region_variant | 2/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.50G>A | p.Gly17Asp | missense_variant, splice_region_variant | 2/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.50G>A | p.Gly17Asp | missense_variant, splice_region_variant | 2/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.50G>A | p.Gly17Asp | missense_variant, splice_region_variant | 2/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome AF: 0.00000214 AC: 3AN: 1404102Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1AN XY: 691562
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2018 | This variant has not been reported in the literature in individuals with CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190620). This variant is present in population databases (rs747083495, ExAC 0.007%). This sequence change replaces glycine with aspartic acid at codon 17 of the CACNA1C protein (p.Gly17Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. 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. 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 19, 2012 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at