2-201706839-C-T

Position:

• chr2-201706839-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020919.4(ALS2):​c.4580+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,613,320 control chromosomes in the GnomAD database, including 26,300 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2673 hom., cov: 31)
  • Exomes 𝑓: 0.16 (23627 hom.)
• Consequence: ALS2 NM_020919.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001254
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.271

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-201706839-C-T is Benign according to our data. Variant chr2-201706839-C-T is described in ClinVar as [Benign]. Clinvar id is 261378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201706839-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALS2	NM_020919.4	c.4580+7G>A		splice_region_variant, intron_variant		ENST00000264276.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALS2	ENST00000264276.11	c.4580+7G>A		splice_region_variant, intron_variant		1	NM_020919.4	P4

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26896 AN: 151858 Hom.: 2670 Cov.: 31

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.169

GnomAD3 exomes AF: 0.204 AC: 50808 AN: 249208 Hom.: 6364 AF XY: 0.210 AC XY: 28449 AN XY: 135204

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.137

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.404

Gnomad SAS exome AF: 0.360

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.165 AC: 241076 AN: 1461344 Hom.: 23627 Cov.: 32 AF XY: 0.171 AC XY: 123975 AN XY: 727006

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.193

Gnomad4 EAS exome AF: 0.396

Gnomad4 SAS exome AF: 0.350

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.185

GnomAD4 genome AF: 0.177 AC: 26925 AN: 151976 Hom.: 2673 Cov.: 31 AF XY: 0.184 AC XY: 13634 AN XY: 74258

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.194

Gnomad4 EAS AF: 0.391

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.172

Alfa AF: 0.130 Hom.: 557

Bravo AF: 0.169

Asia WGS AF: 0.385 AC: 1334 AN: 3478

EpiCase AF: 0.138

EpiControl AF: 0.148

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Infantile-onset ascending hereditary spastic paralysis Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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	-0.87
CADD	Benign	0.24
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs3219169; hg19: chr2-202571562;