chr2-201768859-A-G

Variant names:

• chr2-201768859-A-G
• rs3219153
• NM_020919.4:c.20+7T>C

Variant summary

Our verdict is Benign. The variant received -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. 3/3 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:14
• Conservation: PhyloP100: -0.406
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• ALS2-related motor neuron disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• amyotrophic lateral sclerosis type 2, juvenile

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• infantile-onset ascending hereditary spastic paralysis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• juvenile primary lateral sclerosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ALS2	NM_020919.4	c.20+7T>C		splice_region_variant, intron_variant	Intron 2 of 33	ENST00000264276.11	NP_065970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11	c.20+7T>C		splice_region_variant, intron_variant	Intron 2 of 33	1	NM_020919.4	ENSP00000264276.6

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

GnomAD2 exomes AF: 0.194 AC: 48279 AN: 249128 AF XY: 0.199

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 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

African (AFR) AF: 0.194 AC: 6492 AN: 33398

American (AMR) AF: 0.136 AC: 6079 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4537 AN: 26088

East Asian (EAS) AF: 0.407 AC: 16136 AN: 39632

South Asian (SAS) AF: 0.319 AC: 27497 AN: 86088

European-Finnish (FIN) AF: 0.206 AC: 10997 AN: 53312

Middle Eastern (MID) AF: 0.165 AC: 950 AN: 5758

European-Non Finnish (NFE) AF: 0.130 AC: 144659 AN: 1109180

Other (OTH) AF: 0.176 AC: 10604 AN: 60262

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

African (AFR) AF: 0.186 AC: 7717 AN: 41494

American (AMR) AF: 0.122 AC: 1860 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 598 AN: 3468

East Asian (EAS) AF: 0.403 AC: 2082 AN: 5164

South Asian (SAS) AF: 0.338 AC: 1630 AN: 4818

European-Finnish (FIN) AF: 0.222 AC: 2346 AN: 10550

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9046 AN: 67964

Other (OTH) AF: 0.159 AC: 336 AN: 2110

Alfa AF: 0.145 Hom.: 3336

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 20, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided Benign:2

Jul 06, 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

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	-0.68
CADD	Benign	4.5
DANN	Benign	0.61
PhyloP100		-0.41
PromoterAI		0.022	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3219153; hg19: chr2-202633582; COSMIC: COSV51885356;