2-201706839-C-T

Position:

chr2-201706839-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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 links:

ALS2 (HGNC:):

ALS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
ALS2	NM_020919.4 linkuse as main transcript	c.4580+7G>A		splice_region_variant, intron_variant		ENST00000264276.11	NP_065970.2	Q96Q42-1A8K4R4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11 linkuse as main transcript	c.4580+7G>A		splice_region_variant, intron_variant		1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26896

AN:

151858

Hom.:

2670

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.171

AC XY:

123975

AN XY:

727006

show subpopulations

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.:

AF XY:

0.184

AC XY:

13634

AN XY:

74258

show subpopulations

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:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	- -

Infantile-onset ascending hereditary spastic paralysis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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 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. -
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 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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over