rs3219161

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

15 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 -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 VariationId is 261369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

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

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

GnomAD2 exomes

AF:

0.0959

AC:

23921

AN:

249356

AF XY:

0.0991

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 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

African (AFR)

AF:

0.0675

AC:

2259

AN:

33478

American (AMR)

AF:

0.0378

AC:

1690

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0779

AC:

2037

AN:

26134

East Asian (EAS)

AF:

0.246

AC:

9775

AN:

39698

South Asian (SAS)

AF:

0.131

AC:

11289

AN:

86252

European-Finnish (FIN)

AF:

0.0974

AC:

5197

AN:

53364

Middle Eastern (MID)

AF:

0.0912

AC:

526

AN:

5768

European-Non Finnish (NFE)

AF:

0.0902

AC:

100344

AN:

1111914

Other (OTH)

AF:

0.0974

AC:

5880

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

6685

13370

20054

26739

33424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3822

7644

11466

15288

19110

<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:

0.0866

AC:

13180

AN:

152128

Hom.:

647

Cov.:

AF XY:

0.0893

AC XY:

6642

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0667

AC:

2766

AN:

41484

American (AMR)

AF:

0.0514

AC:

786

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0698

AC:

242

AN:

3468

East Asian (EAS)

AF:

0.242

AC:

1251

AN:

5176

South Asian (SAS)

AF:

0.136

AC:

656

AN:

4820

European-Finnish (FIN)

AF:

0.103

AC:

1087

AN:

10588

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0888

AC:

6035

AN:

67992

Other (OTH)

AF:

0.0790

AC:

167

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

615

1230

1845

2460

3075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

162

324

486

648

810

<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:

0.0842

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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, Academic 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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 17, 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: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

(source)

DANN

Benign

0.71

PhyloP100

0.94

Mutation Taster

=88/12

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