rs386134181
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_020919.4(ALS2):c.1867_1868del(p.Leu623ValfsTer24) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,050 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: 𝑓 0.000013 ( 0 hom., 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: 8.06
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 2-201746695-CAG-C is Pathogenic according to our data. Variant chr2-201746695-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 4406.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.1867_1868del | p.Leu623ValfsTer24 | frameshift_variant | 9/34 | ENST00000264276.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALS2 | ENST00000264276.11 | c.1867_1868del | p.Leu623ValfsTer24 | frameshift_variant | 9/34 | 1 | NM_020919.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461876Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727238
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74346
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Juvenile primary lateral sclerosis Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2001 | - - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Feb 10, 2011 | - - |
Infantile-onset ascending hereditary spastic paralysis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Nov 12, 2018 | - - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at