2-201733390-C-T

Variant names:

• chr2-201733390-C-T
• rs2276615
• NM_020919.4:c.2466G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.0570

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]

ACMG classification

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 rank	MANE	Protein	UniProt
ALS2	NM_020919.4	c.2466G>A	p.Val822Val	synonymous_variant	Exon 13 of 34	ENST00000264276.11	NP_065970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11	c.2466G>A	p.Val822Val	synonymous_variant	Exon 13 of 34	1	NM_020919.4	ENSP00000264276.6

Frequencies

GnomAD3 genomes AF: 0.468 AC: 71090 AN: 151862 Hom.: 19747 Cov.: 32

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

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.: 46 AF XY: 0.579 AC XY: 420628 AN XY: 726788

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.: 32 AF XY: 0.467 AC XY: 34678 AN XY: 74268

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

Submissions by phenotype

not specified Benign:7

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Nov 17, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Infantile-onset ascending hereditary spastic paralysis Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amyotrophic lateral sclerosis type 2, juvenile Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juvenile primary lateral sclerosis Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ALS2-related disorder Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Other links and lift over

dbSNP: rs2276615; hg19: chr2-202598113; COSMIC: COSV51885375;