2-201706839-C-T

Variant names:

• chr2-201706839-C-T
• rs3219169
• NM_020919.4:c.4580+7G>A

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.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:16
• Conservation: PhyloP100: -0.271
• Publications: 9 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=-0.87).
• 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.
• 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 rank	MANE	Protein	UniProt
ALS2	NM_020919.4	c.4580+7G>A		splice_region_variant, intron_variant	Intron 29 of 33	ENST00000264276.11	NP_065970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11	c.4580+7G>A		splice_region_variant, intron_variant	Intron 29 of 33	1	NM_020919.4	ENSP00000264276.6

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

GnomAD2 exomes AF: 0.204 AC: 50808 AN: 249208 AF XY: 0.210

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 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

African (AFR) AF: 0.201 AC: 6742 AN: 33474

American (AMR) AF: 0.142 AC: 6338 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 5039 AN: 26126

East Asian (EAS) AF: 0.396 AC: 15706 AN: 39676

South Asian (SAS) AF: 0.350 AC: 30150 AN: 86238

European-Finnish (FIN) AF: 0.217 AC: 11589 AN: 53370

Middle Eastern (MID) AF: 0.173 AC: 995 AN: 5766

European-Non Finnish (NFE) AF: 0.138 AC: 153350 AN: 1111596

Other (OTH) AF: 0.185 AC: 11167 AN: 60378

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

African (AFR) AF: 0.191 AC: 7933 AN: 41448

American (AMR) AF: 0.133 AC: 2033 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 675 AN: 3472

East Asian (EAS) AF: 0.391 AC: 2016 AN: 5160

South Asian (SAS) AF: 0.366 AC: 1759 AN: 4808

European-Finnish (FIN) AF: 0.231 AC: 2437 AN: 10542

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9597 AN: 67974

Other (OTH) AF: 0.172 AC: 361 AN: 2100

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: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

- -

Sep 20, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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. -

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 13, 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	-0.87
CADD	Benign	0.24
DANN	Benign	0.44
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3219169; hg19: chr2-202571562;