rs730882256

Variant names:

• chr2-201706852-A-AC
• rs730882256
• NM_020919.4:c.4573dupG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_020919.4(ALS2):​c.4573dupG​(p.Val1525GlyfsTer17) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALS2 NM_020919.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.11
• Publications: 3 publications found

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]

ALS2 Gene-Disease associations (from GenCC):

• ALS2-related motor neuron disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• amyotrophic lateral sclerosis type 2, juvenile

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• infantile-onset ascending hereditary spastic paralysis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• juvenile primary lateral sclerosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 2-201706852-A-AC is Pathogenic according to our data. Variant chr2-201706852-A-AC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4	c.4573dupG	p.Val1525GlyfsTer17	frameshift_variant	Exon 29 of 34	ENST00000264276.11	NP_065970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11	c.4573dupG	p.Val1525GlyfsTer17	frameshift_variant	Exon 29 of 34	1	NM_020919.4	ENSP00000264276.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile-onset ascending hereditary spastic paralysis Pathogenic:2

Oct 30, 2019

Cirak Lab, University Hospital Cologne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 04, 2022

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The homozygous p.Val1525GlyfsTer17 variant in ALS2 was identified by our study in 1 individual with infantile-onset ascending hereditary spastic paralysis. The variant has been reported in 3 Turkish individuals with infantile-onset ascending hereditary spastic paralysis (PMID: 24562058, 33155358), segregated with disease in 1 affected relatives from 1 family (PMID: 24562058), and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 183240) as pathogenic by OMIM and as likely pathogenic by Cirak Lab, University Hospital Cologne. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1525 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ALS2 gene is an established disease mechanism in autosomal recessive infantile-onset ascending hereditary spastic paralysis. 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.Val1525GlyfsTer17 variant is pathogenic (PMID: 24562058). In summary, this variant meets criteria to be classified as pathogenic for infantile-onset ascending hereditary spastic paralysis in an autosomal recessive manner based on the predicted impact of the variant, its absence from control populations, and multiple homozygous occurrences in affected individuals. ACMG/AMP Criteria applied: PVS1, PM2, PM3, PP1 (Richards 2015). -

Amyotrophic lateral sclerosis type 2, juvenile Pathogenic:1

Mar 25, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730882256; hg19: chr2-202571575;