2-201733390-C-T

Position:

chr2-201733390-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020919.4(ALS2):c.2466G>A(p.Val822Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 1,612,934 control chromosomes in the GnomAD database, including 274,463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 19749 hom., cov: 32)

Exomes 𝑓: 0.58 ( 254714 hom. )

Consequence

ALS2
NM_020919.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.0570

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:

ALS2 (HGNC:):

ALS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 2-201733390-C-T is Benign according to our data. Variant chr2-201733390-C-T is described in ClinVar as [Benign]. Clinvar id is 261368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201733390-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.057 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALS2	NM_020919.4 linkuse as main transcript	c.2466G>A	p.Val822Val	synonymous_variant	13/34	ENST00000264276.11	NP_065970.2	Q96Q42-1A8K4R4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11 linkuse as main transcript	c.2466G>A	p.Val822Val	synonymous_variant	13/34	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.468

AC:

71090

AN:

151862

Hom.:

19747

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.674

Gnomad AMR

AF:

0.604

Gnomad ASJ

AF:

0.557

Gnomad EAS

AF:

0.355

Gnomad SAS

AF:

0.393

Gnomad FIN

AF:

0.564

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.612

Gnomad OTH

AF:

0.486

GnomAD3 exomes

AF:

0.539

AC:

134219

AN:

248966

Hom.:

38834

AF XY:

0.538

AC XY:

72667

AN XY:

135102

show subpopulations

Gnomad AFR exome

AF:

0.153

Gnomad AMR exome

AF:

0.666

Gnomad ASJ exome

AF:

0.548

Gnomad EAS exome

AF:

0.348

Gnomad SAS exome

AF:

0.399

Gnomad FIN exome

AF:

0.577

Gnomad NFE exome

AF:

0.613

Gnomad OTH exome

AF:

0.558

GnomAD4 exome

AF:

0.582

AC:

850622

AN:

1460954

Hom.:

254714

Cov.:

AF XY:

0.579

AC XY:

420628

AN XY:

726788

show subpopulations

Gnomad4 AFR exome

AF:

0.153

Gnomad4 AMR exome

AF:

0.652

Gnomad4 ASJ exome

AF:

0.548

Gnomad4 EAS exome

AF:

0.355

Gnomad4 SAS exome

AF:

0.408

Gnomad4 FIN exome

AF:

0.579

Gnomad4 NFE exome

AF:

0.617

Gnomad4 OTH exome

AF:

0.545

GnomAD4 genome

AF:

0.468

AC:

71089

AN:

151980

Hom.:

19749

Cov.:

AF XY:

0.467

AC XY:

34678

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.166

Gnomad4 AMR

AF:

0.604

Gnomad4 ASJ

AF:

0.557

Gnomad4 EAS

AF:

0.356

Gnomad4 SAS

AF:

0.392

Gnomad4 FIN

AF:

0.564

Gnomad4 NFE

AF:

0.612

Gnomad4 OTH

AF:

0.482

Alfa

AF:

0.577

Hom.:

33519

Bravo

AF:

0.460

Asia WGS

AF:

0.318

AC:

1108

AN:

3476

EpiCase

AF:

0.614

EpiControl

AF:

0.610

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 17, 2017	- -

Infantile-onset ascending hereditary spastic paralysis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Amyotrophic lateral sclerosis type 2, juvenile

Benign:2

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Juvenile primary lateral sclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

ALS2-related disorder

Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

4.6

DANN

Benign

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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