2-201761714-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020919.4(ALS2):c.280A>G(p.Ile94Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,613,992 control chromosomes in the GnomAD database, including 740 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I94S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.033 ( 97 hom., cov: 32)

Exomes 𝑓: 0.028 ( 643 hom. )

Consequence

ALS2
NM_020919.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.888

Publications

18 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=0.0023296773).

BP6

Variant 2-201761714-T-C is Benign according to our data. Variant chr2-201761714-T-C is described in ClinVar as Benign. ClinVar VariationId is 261370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0333 (5069/152108) while in subpopulation AFR AF = 0.0518 (2148/41482). AF 95% confidence interval is 0.05. There are 97 homozygotes in GnomAd4. There are 2412 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 97 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4 link	c.280A>G	p.Ile94Val	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.280A>G	p.Ile94Val	missense_variant	Exon 4 of 34	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.0333

AC:

5059

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0519

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0240

Gnomad ASJ

AF:

0.0493

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.0244

Gnomad FIN

AF:

0.0241

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0283

Gnomad OTH

AF:

0.0259

GnomAD2 exomes

AF:

0.0251

AC:

6235

AN:

248818

AF XY:

0.0250

show subpopulations

Gnomad AFR exome

AF:

0.0539

Gnomad AMR exome

AF:

0.0145

Gnomad ASJ exome

AF:

0.0480

Gnomad EAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.0220

Gnomad NFE exome

AF:

0.0263

Gnomad OTH exome

AF:

0.0286

GnomAD4 exome

AF:

0.0284

AC:

41510

AN:

1461884

Hom.:

643

Cov.:

AF XY:

0.0280

AC XY:

20344

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0498

AC:

1667

AN:

33480

American (AMR)

AF:

0.0148

AC:

663

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0488

AC:

1275

AN:

26136

East Asian (EAS)

AF:

0.000453

AC:

AN:

39700

South Asian (SAS)

AF:

0.0257

AC:

2214

AN:

86258

European-Finnish (FIN)

AF:

0.0224

AC:

1199

AN:

53418

Middle Eastern (MID)

AF:

0.0186

AC:

107

AN:

5768

European-Non Finnish (NFE)

AF:

0.0294

AC:

32680

AN:

1112004

Other (OTH)

AF:

0.0279

AC:

1687

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2551

5103

7654

10206

12757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1280

2560

3840

5120

6400

<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:

0.0333

AC:

5069

AN:

152108

Hom.:

Cov.:

AF XY:

0.0324

AC XY:

2412

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0518

AC:

2148

AN:

41482

American (AMR)

AF:

0.0240

AC:

367

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0493

AC:

171

AN:

3468

East Asian (EAS)

AF:

0.000966

AC:

AN:

5176

South Asian (SAS)

AF:

0.0243

AC:

117

AN:

4824

European-Finnish (FIN)

AF:

0.0241

AC:

254

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0283

AC:

1926

AN:

68006

Other (OTH)

AF:

0.0304

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

243

486

729

972

1215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0292

Hom.:

300

Bravo

AF:

0.0330

TwinsUK

AF:

0.0329

AC:

122

ALSPAC

AF:

0.0306

AC:

118

ESP6500AA

AF:

0.0501

AC:

198

ESP6500EA

AF:

0.0256

AC:

213

ExAC

AF:

0.0249

AC:

3008

Asia WGS

AF:

0.0420

AC:

146

AN:

3478

EpiCase

AF:

0.0260

EpiControl

AF:

0.0249

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 13, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

not provided

Benign:3

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Aug 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28430856, 18810511, 14676054, 25588603) -

Infantile-onset ascending hereditary spastic paralysis

Benign:1

Jan 31, 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

Hereditary spastic paraplegia

Benign:1

Nov 23, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

0.055

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.090

T;.;.;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.46

T;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.15

N;N;.;.

PhyloP100

0.89

PrimateAI

Benign

0.39

PROVEAN

Benign

0.28

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;.;.

Polyphen

0.0

B;B;.;.

Vest4

0.020

MPC

0.19

ClinPred

0.00064

GERP RS

2.9

Varity_R

0.014

gMVP

0.28

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