rs200706696

Positions:

chr2-201726526-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020919.4(ALS2):c.3206G>A(p.Gly1069Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,614,148 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 3 hom. )

Consequence

ALS2
NM_020919.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 7.50

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.033438057).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALS2	NM_020919.4 linkuse as main transcript	c.3206G>A	p.Gly1069Glu	missense_variant	19/34	ENST00000264276.11	NP_065970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11 linkuse as main transcript	c.3206G>A	p.Gly1069Glu	missense_variant	19/34	1	NM_020919.4	ENSP00000264276	P4	Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000682

AC:

170

AN:

249412

Hom.:

AF XY:

0.000673

AC XY:

AN XY:

135306

show subpopulations

Gnomad AFR exome

AF:

0.000581

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.0117

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000239

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.000425

AC:

622

AN:

1461830

Hom.:

Cov.:

AF XY:

0.000437

AC XY:

318

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.0128

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000177

Gnomad4 OTH exome

AF:

0.000960

GnomAD4 genome

AF:

0.000565

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000829

Hom.:

Bravo

AF:

0.000646

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000269

AC:

ESP6500EA

AF:

0.000734

AC:

ExAC

AF:

0.000513

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 2, juvenile

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Amyotrophic lateral sclerosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

UM ALS/MND Lab, University Of Malta

Jul 31, 2020

The frequency of the Gly1069Glu variant in the ALS2 gene was 0.000376 for ALS cases and 0 for controls in the Project MinE ALS case-control dataset, with this supporting evidence favouring its classification as pathogenic. -

ALS2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Mar 07, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2020

Reported in an individual with clinical diagnosis of hereditary spastic paraplegia (Morais et al., 2017) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function This variant is associated with the following publications: (PMID: 28832565, 32397312) -

Infantile-onset ascending hereditary spastic paralysis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.033

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

2.9

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.70

MVP

0.91

MPC

0.96

ClinPred

0.099

GERP RS

5.7

Varity_R

0.86

gMVP

0.88

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over