2-201705269-A-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.4627-69T>A 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 1,501,258 control chromosomes in the GnomAD database, including 639,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.89 ( 61104 hom., cov: 32)

Exomes 𝑓: 0.93 ( 578227 hom. )

Consequence

ALS2
NM_020919.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.310

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=-0.8).

BP6

Variant 2-201705269-A-T is Benign according to our data. Variant chr2-201705269-A-T is described in ClinVar as Benign. ClinVar VariationId is 1188975.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.4627-69T>A		intron_variant	Intron 30 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.4627-69T>A		intron_variant	Intron 30 of 33	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.894

AC:

136086

AN:

152170

Hom.:

61057

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

GnomAD4 exome

AF:

0.925

AC:

1248418

AN:

1348970

Hom.:

578227

Cov.:

AF XY:

0.927

AC XY:

627907

AN XY:

677316

show subpopulations

African (AFR)

AF:

0.825

AC:

25581

AN:

31006

American (AMR)

AF:

0.890

AC:

39531

AN:

44438

Ashkenazi Jewish (ASJ)

AF:

0.915

AC:

23285

AN:

25448

East Asian (EAS)

AF:

0.991

AC:

38611

AN:

38968

South Asian (SAS)

AF:

0.959

AC:

80325

AN:

83782

European-Finnish (FIN)

AF:

0.954

AC:

50813

AN:

53276

Middle Eastern (MID)

AF:

0.904

AC:

5039

AN:

5574

European-Non Finnish (NFE)

AF:

0.924

AC:

933063

AN:

1009880

Other (OTH)

AF:

0.922

AC:

52170

AN:

56598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

5089

10178

15266

20355

25444

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18830

37660

56490

75320

94150

<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:

136192

AN:

152288

Hom.:

61104

Cov.:

AF XY:

0.898

AC XY:

66859

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.819

AC:

34002

AN:

41514

American (AMR)

AF:

0.883

AC:

13503

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.914

AC:

3173

AN:

3472

East Asian (EAS)

AF:

0.985

AC:

5114

AN:

5194

South Asian (SAS)

AF:

0.959

AC:

4632

AN:

4828

European-Finnish (FIN)

AF:

0.961

AC:

10208

AN:

10626

Middle Eastern (MID)

AF:

0.878

AC:

258

AN:

294

European-Non Finnish (NFE)

AF:

0.919

AC:

62545

AN:

68034

Other (OTH)

AF:

0.881

AC:

1862

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

740

1480

2219

2959

3699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

906

1812

2718

3624

4530

<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:

0.903

Hom.:

7746

Bravo

AF:

0.885

Asia WGS

AF:

0.958

AC:

3331

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 03, 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

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

-0.80

CADD

Benign

3.5

(source)

DANN

Benign

0.75

PhyloP100

0.31

Mutation Taster

=100/0

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