2-201704570-GA-G
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_020919.4(ALS2):c.4721del(p.Val1574AlafsTer44) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
ALS2
NM_020919.4 frameshift
NM_020919.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.25
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 11 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 2-201704570-GA-G is Pathogenic according to our data. Variant chr2-201704570-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 4412.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALS2 | NM_020919.4 | c.4721del | p.Val1574AlafsTer44 | frameshift_variant | 32/34 | ENST00000264276.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALS2 | ENST00000264276.11 | c.4721del | p.Val1574AlafsTer44 | frameshift_variant | 32/34 | 1 | NM_020919.4 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461824Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727210
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Infantile-onset ascending hereditary spastic paralysis Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2003 | - - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Feb 10, 2011 | - - |
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