rs878855058
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_020919.4(ALS2):c.1425_1428del(p.Gly477AlafsTer19) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000274 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
ALS2
NM_020919.4 frameshift
NM_020919.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.10
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 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-201757444-CCTCT-C is Pathogenic according to our data. Variant chr2-201757444-CCTCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 241308.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALS2 | NM_020919.4 | c.1425_1428del | p.Gly477AlafsTer19 | frameshift_variant | 5/34 | ENST00000264276.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALS2 | ENST00000264276.11 | c.1425_1428del | p.Gly477AlafsTer19 | frameshift_variant | 5/34 | 1 | NM_020919.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461782Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727192
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Infantile-onset ascending hereditary spastic paralysis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 241308). This premature translational stop signal has been observed in individual(s) with autosomal recessive infantile-onset ascending hereditary spastic paraplegia (PMID: 25302125). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly477Alafs*19) in the ALS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALS2 are known to be pathogenic (PMID: 11586298, 24315819). - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at