rs34946105

Positions:

chr2-201715791-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_020919.4(ALS2):c.3885G>A(p.Ala1295Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,614,196 control chromosomes in the GnomAD database, including 972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 83 hom., cov: 32)

Exomes 𝑓: 0.032 ( 889 hom. )

Consequence

ALS2
NM_020919.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -1.30

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 2-201715791-C-T is Benign according to our data. Variant chr2-201715791-C-T is described in ClinVar as [Benign]. Clinvar id is 261374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201715791-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.3 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0265 (4039/152322) while in subpopulation SAS AF= 0.0359 (173/4824). AF 95% confidence interval is 0.0325. There are 83 homozygotes in gnomad4. There are 2001 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 83 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALS2	NM_020919.4 linkuse as main transcript	c.3885G>A	p.Ala1295Ala	synonymous_variant	25/34	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.3885G>A	p.Ala1295Ala	synonymous_variant	25/34	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.0266

AC:

4044

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00555

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.0230

Gnomad ASJ

AF:

0.0948

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0362

Gnomad FIN

AF:

0.0491

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0337

Gnomad OTH

AF:

0.0344

GnomAD3 exomes

AF:

0.0333

AC:

8296

AN:

249356

Hom.:

173

AF XY:

0.0345

AC XY:

4673

AN XY:

135294

show subpopulations

Gnomad AFR exome

AF:

0.00484

Gnomad AMR exome

AF:

0.0180

Gnomad ASJ exome

AF:

0.0944

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0372

Gnomad FIN exome

AF:

0.0493

Gnomad NFE exome

AF:

0.0374

Gnomad OTH exome

AF:

0.0367

GnomAD4 exome

AF:

0.0321

AC:

46968

AN:

1461874

Hom.:

889

Cov.:

AF XY:

0.0327

AC XY:

23771

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00463

Gnomad4 AMR exome

AF:

0.0183

Gnomad4 ASJ exome

AF:

0.0922

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0375

Gnomad4 FIN exome

AF:

0.0477

Gnomad4 NFE exome

AF:

0.0319

Gnomad4 OTH exome

AF:

0.0335

GnomAD4 genome

AF:

0.0265

AC:

4039

AN:

152322

Hom.:

Cov.:

AF XY:

0.0269

AC XY:

2001

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00553

Gnomad4 AMR

AF:

0.0229

Gnomad4 ASJ

AF:

0.0948

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0359

Gnomad4 FIN

AF:

0.0491

Gnomad4 NFE

AF:

0.0337

Gnomad4 OTH

AF:

0.0340

Alfa

AF:

0.0347

Hom.:

Bravo

AF:

0.0244

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0353

EpiControl

AF:

0.0427

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2023	- -
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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2019	- -

Infantile-onset ascending hereditary spastic paralysis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Amyotrophic lateral sclerosis type 2, juvenile

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. -

ALS2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.1

DANN

Benign

0.82

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