rs121908138
Positions:
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 (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
ALS2
NM_020919.4 missense
NM_020919.4 missense
Scores
13
4
2
Clinical Significance
Conservation
PhyloP100: 7.71
Genes affected
ALS2 (HGNC:443): (alsin Rho guanine nucleotide exchange factor ALS2) The protein encoded by this gene contains an ATS1/RCC1-like domain, a RhoGEF domain, and a vacuolar protein sorting 9 (VPS9) domain, all of which are guanine-nucleotide exchange factors that activate members of the Ras superfamily of GTPases. The protein functions as a guanine nucleotide exchange factor for the small GTPase RAB5. The protein localizes with RAB5 on early endosomal compartments, and functions as a modulator for endosomal dynamics. Mutations in this gene result in several forms of juvenile lateral sclerosis and infantile-onset ascending spastic paralysis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 2-201761524-C-T is Pathogenic according to our data. Variant chr2-201761524-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALS2 | NM_020919.4 | c.470G>A | p.Cys157Tyr | missense_variant | 4/34 | ENST00000264276.11 | NP_065970.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALS2 | ENST00000264276.11 | c.470G>A | p.Cys157Tyr | missense_variant | 4/34 | 1 | NM_020919.4 | ENSP00000264276 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 38
GnomAD4 exome
Cov.:
38
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Infantile-onset ascending hereditary spastic paralysis Pathogenic:4
Likely pathogenic, criteria provided, single submitter | research | Cirak Lab, University Hospital Cologne | Oct 30, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2006 | - - |
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). - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Benign
T;D
Polyphen
D;D
Vest4
MutPred
Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at