NM_020919.4:c.470G>A

Variant names:

• chr2-201761524-C-T
• rs121908138
• NM_020919.4:c.470G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C157G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALS2 NM_020919.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.71
• Publications: 8 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 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 VariationId is 4415.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.470G>A	p.Cys157Tyr	missense_variant	Exon 4 of 34	ENST00000264276.11	NP_065970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11	c.470G>A	p.Cys157Tyr	missense_variant	Exon 4 of 34	1	NM_020919.4	ENSP00000264276.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile-onset ascending hereditary spastic paralysis Pathogenic:4

May 04, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

Oct 30, 2019

Cirak Lab, University Hospital Cologne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 10, 2011

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Jun 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALS2: PM2, PM3, PM5, PP3, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.7	H;H
PhyloP100		7.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.020	D;D
Sift4G	Benign	0.17	T;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.96		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.96
MPC		1.1
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.77
gMVP		0.98
Mutation Taster		=7/93	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: rs121908138; hg19: chr2-202626247;