chr2-201760892-C-T

Position:

chr2-201760892-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.1102G>A(p.Val368Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.902 in 1,612,470 control chromosomes in the GnomAD database, including 657,112 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.87 ( 58538 hom., cov: 32)

Exomes 𝑓: 0.90 ( 598574 hom. )

Consequence

ALS2
NM_020919.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -1.95

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2400155E-6).

BP6

Variant 2-201760892-C-T is Benign according to our data. Variant chr2-201760892-C-T is described in ClinVar as [Benign]. Clinvar id is 261364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201760892-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALS2	NM_020919.4 link	c.1102G>A	p.Val368Met	missense_variant	4/34	ENST00000264276.11	NP_065970.2	Q96Q42-1A8K4R4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11 link	c.1102G>A	p.Val368Met	missense_variant	4/34	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.875

AC:

133098

AN:

152118

Hom.:

58495

Cov.:

show subpopulations

Gnomad AFR

AF:

0.789

Gnomad AMI

AF:

0.941

Gnomad AMR

AF:

0.909

Gnomad ASJ

AF:

0.902

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.951

Gnomad FIN

AF:

0.926

Gnomad MID

AF:

0.854

Gnomad NFE

AF:

0.895

Gnomad OTH

AF:

0.866

GnomAD3 exomes

AF:

0.913

AC:

227612

AN:

249212

Hom.:

104199

AF XY:

0.916

AC XY:

123783

AN XY:

135192

show subpopulations

Gnomad AFR exome

AF:

0.783

Gnomad AMR exome

AF:

0.934

Gnomad ASJ exome

AF:

0.903

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.951

Gnomad FIN exome

AF:

0.921

Gnomad NFE exome

AF:

0.901

Gnomad OTH exome

AF:

0.909

GnomAD4 exome

AF:

0.905

AC:

1321448

AN:

1460234

Hom.:

598574

Cov.:

AF XY:

0.906

AC XY:

658222

AN XY:

726114

show subpopulations

Gnomad4 AFR exome

AF:

0.788

Gnomad4 AMR exome

AF:

0.931

Gnomad4 ASJ exome

AF:

0.902

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.948

Gnomad4 FIN exome

AF:

0.921

Gnomad4 NFE exome

AF:

0.900

Gnomad4 OTH exome

AF:

0.903

GnomAD4 genome

AF:

0.875

AC:

133197

AN:

152236

Hom.:

58538

Cov.:

AF XY:

0.879

AC XY:

65395

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.789

Gnomad4 AMR

AF:

0.909

Gnomad4 ASJ

AF:

0.902

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.952

Gnomad4 FIN

AF:

0.926

Gnomad4 NFE

AF:

0.895

Gnomad4 OTH

AF:

0.868

Alfa

AF:

0.895

Hom.:

157365

Bravo

AF:

0.870

TwinsUK

AF:

0.896

AC:

3324

ALSPAC

AF:

0.904

AC:

3483

ESP6500AA

AF:

0.782

AC:

2997

ESP6500EA

AF:

0.898

AC:

7442

ExAC

AF:

0.910

AC:

109982

Asia WGS

AF:

0.971

AC:

3375

AN:

3478

EpiCase

AF:

0.894

EpiControl

AF:

0.897

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

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 17, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Infantile-onset ascending hereditary spastic paralysis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 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 12, 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 12, 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

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.0050

DANN

Benign

0.50

DEOGEN2

Benign

0.081

T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.076

T;T

MetaRNN

Benign

0.0000012

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.060

N;N

REVEL

Benign

0.021

Sift

Benign

0.19

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0

B;B

Vest4

0.024

MPC

0.23

ClinPred

0.0022

GERP RS

-3.8

Varity_R

0.019

gMVP

0.17

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