2-201761524-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_020919.4(ALS2):c.470G>A(p.Cys157Tyr) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C157G) has been classified as Uncertain significance.
Frequency
Consequence
NM_020919.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALS2 | NM_020919.4 | c.470G>A | p.Cys157Tyr | missense_variant | 4/34 | ENST00000264276.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALS2 | ENST00000264276.11 | c.470G>A | p.Cys157Tyr | missense_variant | 4/34 | 1 | NM_020919.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 38
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Infantile-onset ascending hereditary spastic paralysis Pathogenic:4
Pathogenic, no assertion criteria provided | curation | GeneReviews | Feb 10, 2011 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 04, 2022 | The homozygous p.Cys157Tyr variant in ALS2 was identified by our study in 2 siblings with infantile-onset ascending hereditary spastic paralysis. The variant has been reported in three Turkish individuals with infantile-onset ascending hereditary spastic paralysis (PMID: 16718699, 33155358), segregated with disease in 2 affected relatives from 2 families (PMID: 16718699, unpublished data), and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 4415) and has been interpreted as pathogenic by OMIM, GeneReviews, and CeGaT Praxis fuer Humangenetik Tuebingen, and as likely pathogenic by Cirak Lab, University Hospital Cologne. In vitro functional studies provide some evidence that the p.Cys157Tyr variant may impact protein function (PMID: 30224357, 21300063, 16718699). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in 3 affected homozygotes, and in 3 individuals with infantile-onset ascending hereditary spastic paralysis increases the likelihood that the p.Cys157Tyr variant is pathogenic (PMID: 16718699). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3_moderate, PP3, PM3, PP1 (Richards 2015). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2006 | - - |
Likely pathogenic, criteria provided, single submitter | research | Cirak Lab, University Hospital Cologne | Oct 30, 2019 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | ALS2: PM2, PM3, PM5, PP3, PS3:Supporting - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at