rs3219161

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_020919.4(ALS2):c.2796C>T(p.Ser932Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0943 in 1,613,840 control chromosomes in the GnomAD database, including 8,091 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.087 ( 647 hom., cov: 32)

Exomes 𝑓: 0.095 ( 7444 hom. )

Consequence

ALS2
NM_020919.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.943

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 2-201728557-G-A is Benign according to our data. Variant chr2-201728557-G-A is described in ClinVar as [Benign]. Clinvar id is 261369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201728557-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.943 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4 link	c.2796C>T	p.Ser932Ser	synonymous_variant	Exon 15 of 34	ENST00000264276.11	NP_065970.2	Q96Q42-1A8K4R4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11 link	c.2796C>T	p.Ser932Ser	synonymous_variant	Exon 15 of 34	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.0867

AC:

13175

AN:

152010

Hom.:

646

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0666

Gnomad AMI

AF:

0.172

Gnomad AMR

AF:

0.0516

Gnomad ASJ

AF:

0.0698

Gnomad EAS

AF:

0.242

Gnomad SAS

AF:

0.136

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0888

Gnomad OTH

AF:

0.0798

GnomAD3 exomes

AF:

0.0959

AC:

23921

AN:

249356

Hom.:

1429

AF XY:

0.0991

AC XY:

13412

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.0668

Gnomad AMR exome

AF:

0.0355

Gnomad ASJ exome

AF:

0.0771

Gnomad EAS exome

AF:

0.242

Gnomad SAS exome

AF:

0.133

Gnomad FIN exome

AF:

0.0962

Gnomad NFE exome

AF:

0.0870

Gnomad OTH exome

AF:

0.0887

GnomAD4 exome

AF:

0.0951

AC:

138997

AN:

1461712

Hom.:

7444

Cov.:

AF XY:

0.0960

AC XY:

69793

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.0675

Gnomad4 AMR exome

AF:

0.0378

Gnomad4 ASJ exome

AF:

0.0779

Gnomad4 EAS exome

AF:

0.246

Gnomad4 SAS exome

AF:

0.131

Gnomad4 FIN exome

AF:

0.0974

Gnomad4 NFE exome

AF:

0.0902

Gnomad4 OTH exome

AF:

0.0974

GnomAD4 genome

AF:

0.0866

AC:

13180

AN:

152128

Hom.:

647

Cov.:

AF XY:

0.0893

AC XY:

6642

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0667

Gnomad4 AMR

AF:

0.0514

Gnomad4 ASJ

AF:

0.0698

Gnomad4 EAS

AF:

0.242

Gnomad4 SAS

AF:

0.136

Gnomad4 FIN

AF:

0.103

Gnomad4 NFE

AF:

0.0888

Gnomad4 OTH

AF:

0.0790

Alfa

AF:

0.0842

Hom.:

317

Bravo

AF:

0.0819

Asia WGS

AF:

0.181

AC:

629

AN:

3478

EpiCase

AF:

0.0875

EpiControl

AF:

0.0833

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

- -

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

- -

Oct 01, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Infantile-onset ascending hereditary spastic paralysis

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amyotrophic lateral sclerosis type 2, juvenile

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. -

ALS2-related disorder

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

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