4-89835580-C-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_000345.4(SNCA):c.88G>C(p.Ala30Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_000345.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal dominant Parkinson disease 1 Pathogenic:2
- -
This sequence change is predicted to replace alanine with proline at codon 30 of the SNCA protein (p.(Ala30Pro)). The alanine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in an N-terminal domain helix. There is a small physicochemical difference between alanine and glycine. The variant is absent in a large population cohort (PM2; gnomAD v2.1 and v3.0). It has been shown to co-segregate with Parkinson disease in a single family (PP1; PMID: 11376188). Additionally, mouse models of the variant recapitulate the human Parkinson disease phenotype and brain pathology (PS3; PMID: 21559878, 31267130). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as a LIKELY PATHOGENIC. Following criteria are met: PS3, PM2, PP1, PP3. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at