rs3219153

chr2-201768859-A-Gchr2-201768859-A-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.20+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,610,464 control chromosomes in the GnomAD database, including 23,992 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2488 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21504 hom.)
• Consequence: ALS2 NM_020919.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004604
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.406

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=-0.68).
• BP6: Variant 2-201768859-A-G is Benign according to our data. Variant chr2-201768859-A-G is described in ClinVar as [Benign]. Clinvar id is 261367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201768859-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALS2	NM_020919.4	c.20+7T>C		splice_region_variant, intron_variant		ENST00000264276.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALS2	ENST00000264276.11	c.20+7T>C		splice_region_variant, intron_variant		1	NM_020919.4	P4

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25708 AN: 151946 Hom.: 2488 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.159

GnomAD3 exomes AF: 0.194 AC: 48279 AN: 249128 Hom.: 5845 AF XY: 0.199 AC XY: 26898 AN XY: 135190

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.411

Gnomad SAS exome AF: 0.329

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.156 AC: 227951 AN: 1458402 Hom.: 21504 Cov.: 31 AF XY: 0.161 AC XY: 116933 AN XY: 725704

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.136

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.407

Gnomad4 SAS exome AF: 0.319

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.169 AC: 25725 AN: 152062 Hom.: 2488 Cov.: 32 AF XY: 0.175 AC XY: 13022 AN XY: 74332

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.172

Gnomad4 EAS AF: 0.403

Gnomad4 SAS AF: 0.338

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.159

Alfa AF: 0.145 Hom.: 2773

Bravo AF: 0.163

Asia WGS AF: 0.372 AC: 1288 AN: 3474

EpiCase AF: 0.129

EpiControl AF: 0.137

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2019	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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	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 Disorders 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	4.5
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.0020
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: rs3219153; hg19: chr2-202633582; COSMIC: COSV51885356;