2-201760892-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Publications

51 publications found

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 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

ALS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 261364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4 link	c.1102G>A	p.Val368Met	missense_variant	Exon 4 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.1102G>A	p.Val368Met	missense_variant	Exon 4 of 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

GnomAD2 exomes

AF:

0.913

AC:

227612

AN:

249212

AF XY:

0.916

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 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

African (AFR)

AF:

0.788

AC:

26340

AN:

33418

American (AMR)

AF:

0.931

AC:

41566

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.902

AC:

23564

AN:

26120

East Asian (EAS)

AF:

1.00

AC:

39644

AN:

39660

South Asian (SAS)

AF:

0.948

AC:

81766

AN:

86234

European-Finnish (FIN)

AF:

0.921

AC:

49178

AN:

53406

Middle Eastern (MID)

AF:

0.877

AC:

5054

AN:

5764

European-Non Finnish (NFE)

AF:

0.900

AC:

999844

AN:

1110634

Other (OTH)

AF:

0.903

AC:

54492

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

6962

13924

20886

27848

34810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21460

42920

64380

85840

107300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.875

AC:

133197

AN:

152236

Hom.:

58538

Cov.:

AF XY:

0.879

AC XY:

65395

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.789

AC:

32744

AN:

41498

American (AMR)

AF:

0.909

AC:

13907

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.902

AC:

3131

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5183

AN:

5188

South Asian (SAS)

AF:

0.952

AC:

4595

AN:

4828

European-Finnish (FIN)

AF:

0.926

AC:

9817

AN:

10606

Middle Eastern (MID)

AF:

0.857

AC:

252

AN:

294

European-Non Finnish (NFE)

AF:

0.895

AC:

60876

AN:

68022

Other (OTH)

AF:

0.868

AC:

1834

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

823

1645

2468

3290

4113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

896

1792

2688

3584

4480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.890

Hom.:

232228

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

Genome Diagnostics Laboratory, Amsterdam University 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

- -

Clinical Genetics, Academic 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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

not provided

Benign:3

Nov 17, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Jan 12, 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. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 12, 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

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.0050

(source)

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

PhyloP100

-2.0

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

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over