rs3219170

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.4581-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 1,485,640 control chromosomes in the GnomAD database, including 631,949 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.89 ( 61068 hom., cov: 32)

Exomes 𝑓: 0.92 ( 570881 hom. )

Consequence

ALS2
NM_020919.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.198

Publications

9 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 (BayesDel_noAF=-0.9).

BP6

Variant 2-201705509-A-G is Benign according to our data. Variant chr2-201705509-A-G is described in ClinVar as Benign. ClinVar VariationId is 261379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4 link	c.4581-48T>C		intron_variant	Intron 29 of 33	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.4581-48T>C		intron_variant	Intron 29 of 33	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.894

AC:

136002

AN:

152088

Hom.:

61021

Cov.:

show subpopulations

Gnomad AFR

AF:

0.819

Gnomad AMI

AF:

0.981

Gnomad AMR

AF:

0.882

Gnomad ASJ

AF:

0.914

Gnomad EAS

AF:

0.984

Gnomad SAS

AF:

0.959

Gnomad FIN

AF:

0.961

Gnomad MID

AF:

0.870

Gnomad NFE

AF:

0.919

Gnomad OTH

AF:

0.880

GnomAD2 exomes

AF:

0.923

AC:

221992

AN:

240488

AF XY:

0.928

show subpopulations

Gnomad AFR exome

AF:

0.821

Gnomad AMR exome

AF:

0.893

Gnomad ASJ exome

AF:

0.916

Gnomad EAS exome

AF:

0.986

Gnomad FIN exome

AF:

0.954

Gnomad NFE exome

AF:

0.921

Gnomad OTH exome

AF:

0.920

GnomAD4 exome

AF:

0.925

AC:

1233347

AN:

1333434

Hom.:

570881

Cov.:

AF XY:

0.927

AC XY:

621142

AN XY:

670362

show subpopulations

African (AFR)

AF:

0.825

AC:

25139

AN:

30478

American (AMR)

AF:

0.890

AC:

39194

AN:

44058

Ashkenazi Jewish (ASJ)

AF:

0.914

AC:

23084

AN:

25258

East Asian (EAS)

AF:

0.991

AC:

38384

AN:

38744

South Asian (SAS)

AF:

0.959

AC:

79229

AN:

82654

European-Finnish (FIN)

AF:

0.954

AC:

50627

AN:

53080

Middle Eastern (MID)

AF:

0.904

AC:

4352

AN:

4816

European-Non Finnish (NFE)

AF:

0.923

AC:

921869

AN:

998496

Other (OTH)

AF:

0.922

AC:

51469

AN:

55850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

4692

9383

14075

18766

23458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18568

37136

55704

74272

92840

<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:

0.894

AC:

136108

AN:

152206

Hom.:

61068

Cov.:

AF XY:

0.898

AC XY:

66792

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.819

AC:

33995

AN:

41514

American (AMR)

AF:

0.882

AC:

13486

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.914

AC:

3171

AN:

3470

East Asian (EAS)

AF:

0.985

AC:

5106

AN:

5186

South Asian (SAS)

AF:

0.959

AC:

4621

AN:

4818

European-Finnish (FIN)

AF:

0.961

AC:

10196

AN:

10612

Middle Eastern (MID)

AF:

0.878

AC:

258

AN:

294

European-Non Finnish (NFE)

AF:

0.919

AC:

62524

AN:

68006

Other (OTH)

AF:

0.880

AC:

1856

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

723

1446

2170

2893

3616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

904

1808

2712

3616

4520

<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:

0.904

Hom.:

12044

Bravo

AF:

0.885

Asia WGS

AF:

0.958

AC:

3327

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Infantile-onset ascending hereditary spastic paralysis

Benign:1

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

- -

Amyotrophic lateral sclerosis type 2, juvenile

Benign:1

Jul 14, 2021

Genome-Nilou Lab

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

-0.90

CADD

Benign

4.1

(source)

DANN

Benign

0.78

PhyloP100

0.20

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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