2-201711098-G-A

Position:

• chr2-201711098-G-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.4015C>T​(p.Leu1339=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 1,597,622 control chromosomes in the GnomAD database, including 679,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61052 hom., cov: 31)
  • Exomes 𝑓: 0.92 (618575 hom.)
• Consequence: ALS2 NM_020919.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -2.01

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=-0.76).
• BP6: Variant 2-201711098-G-A is Benign according to our data. Variant chr2-201711098-G-A is described in ClinVar as [Benign]. Clinvar id is 261377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201711098-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALS2	NM_020919.4	c.4015C>T	p.Leu1339=	synonymous_variant	26/34	ENST00000264276.11	NP_065970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11	c.4015C>T	p.Leu1339=	synonymous_variant	26/34	1	NM_020919.4	ENSP00000264276	P4

Frequencies

GnomAD3 genomes AF: 0.894 AC: 135975 AN: 152064 Hom.: 61006 Cov.: 31

Gnomad AFR AF: 0.818

Gnomad AMI AF: 0.981

Gnomad AMR AF: 0.882

Gnomad ASJ AF: 0.914

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.959

Gnomad FIN AF: 0.961

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.920

Gnomad OTH AF: 0.879

GnomAD3 exomes AF: 0.923 AC: 229663 AN: 248828 Hom.: 106194 AF XY: 0.927 AC XY: 125225 AN XY: 135024

Gnomad AFR exome AF: 0.819

Gnomad AMR exome AF: 0.892

Gnomad ASJ exome AF: 0.916

Gnomad EAS exome AF: 0.986

Gnomad SAS exome AF: 0.960

Gnomad FIN exome AF: 0.955

Gnomad NFE exome AF: 0.921

Gnomad OTH exome AF: 0.919

GnomAD4 exome AF: 0.925 AC: 1336609 AN: 1445440 Hom.: 618575 Cov.: 27 AF XY: 0.926 AC XY: 667121 AN XY: 720206

Gnomad4 AFR exome AF: 0.823

Gnomad4 AMR exome AF: 0.889

Gnomad4 ASJ exome AF: 0.915

Gnomad4 EAS exome AF: 0.991

Gnomad4 SAS exome AF: 0.958

Gnomad4 FIN exome AF: 0.954

Gnomad4 NFE exome AF: 0.923

Gnomad4 OTH exome AF: 0.921

GnomAD4 genome AF: 0.894 AC: 136079 AN: 152182 Hom.: 61052 Cov.: 31 AF XY: 0.898 AC XY: 66780 AN XY: 74394

Gnomad4 AFR AF: 0.818

Gnomad4 AMR AF: 0.882

Gnomad4 ASJ AF: 0.914

Gnomad4 EAS AF: 0.985

Gnomad4 SAS AF: 0.959

Gnomad4 FIN AF: 0.961

Gnomad4 NFE AF: 0.920

Gnomad4 OTH AF: 0.880

Alfa AF: 0.912 Hom.: 83219

Bravo AF: 0.885

Asia WGS AF: 0.957 AC: 3329 AN: 3478

EpiCase AF: 0.915

EpiControl AF: 0.918

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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

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

Amyotrophic lateral sclerosis type 2, juvenile Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

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 13, 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	-0.76
CADD	Benign	0.28
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3219168; hg19: chr2-202575821;