rs3219167

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.4004+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.83 in 1,613,194 control chromosomes in the GnomAD database, including 556,568 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.82 ( 50739 hom., cov: 32)

Exomes 𝑓: 0.83 ( 505829 hom. )

Consequence

ALS2
NM_020919.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.859

Publications

11 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=-0.81).

BP6

Variant 2-201715647-G-A is Benign according to our data. Variant chr2-201715647-G-A is described in ClinVar as [Benign]. Clinvar id is 261375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4 link	c.4004+25C>T		intron_variant	Intron 25 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.4004+25C>T		intron_variant	Intron 25 of 33	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.816

AC:

124110

AN:

152064

Hom.:

50695

Cov.:

show subpopulations

Gnomad AFR

AF:

0.780

Gnomad AMI

AF:

0.808

Gnomad AMR

AF:

0.834

Gnomad ASJ

AF:

0.844

Gnomad EAS

AF:

0.747

Gnomad SAS

AF:

0.841

Gnomad FIN

AF:

0.856

Gnomad MID

AF:

0.759

Gnomad NFE

AF:

0.831

Gnomad OTH

AF:

0.807

GnomAD2 exomes

AF:

0.831

AC:

205194

AN:

246858

AF XY:

0.833

show subpopulations

Gnomad AFR exome

AF:

0.782

Gnomad AMR exome

AF:

0.858

Gnomad ASJ exome

AF:

0.839

Gnomad EAS exome

AF:

0.749

Gnomad FIN exome

AF:

0.856

Gnomad NFE exome

AF:

0.835

Gnomad OTH exome

AF:

0.832

GnomAD4 exome

AF:

0.832

AC:

1214904

AN:

1461012

Hom.:

505829

Cov.:

AF XY:

0.832

AC XY:

605058

AN XY:

726826

show subpopulations

African (AFR)

AF:

0.785

AC:

26257

AN:

33466

American (AMR)

AF:

0.853

AC:

38129

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.837

AC:

21856

AN:

26126

East Asian (EAS)

AF:

0.748

AC:

29704

AN:

39686

South Asian (SAS)

AF:

0.842

AC:

72591

AN:

86224

European-Finnish (FIN)

AF:

0.854

AC:

45626

AN:

53412

Middle Eastern (MID)

AF:

0.818

AC:

4716

AN:

5768

European-Non Finnish (NFE)

AF:

0.833

AC:

926068

AN:

1111260

Other (OTH)

AF:

0.828

AC:

49957

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

9675

19350

29024

38699

48374

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.816

AC:

124209

AN:

152182

Hom.:

50739

Cov.:

AF XY:

0.817

AC XY:

60810

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.780

AC:

32358

AN:

41496

American (AMR)

AF:

0.834

AC:

12758

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.844

AC:

2930

AN:

3472

East Asian (EAS)

AF:

0.747

AC:

3869

AN:

5178

South Asian (SAS)

AF:

0.841

AC:

4054

AN:

4822

European-Finnish (FIN)

AF:

0.856

AC:

9078

AN:

10600

Middle Eastern (MID)

AF:

0.769

AC:

226

AN:

294

European-Non Finnish (NFE)

AF:

0.831

AC:

56495

AN:

68002

Other (OTH)

AF:

0.808

AC:

1707

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1176

2351

3527

4702

5878

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.830

Hom.:

69798

Bravo

AF:

0.812

Asia WGS

AF:

0.788

AC:

2739

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

- -

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

-0.81

CADD

Benign

0.45

(source)

DANN

Benign

0.50

PhyloP100

-0.86

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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rs3219167

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