NM_020919.4:c.1114-27A>G

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.1114-27A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,504,302 control chromosomes in the GnomAD database, including 23,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2498 hom., cov: 32)

Exomes 𝑓: 0.16 ( 20770 hom. )

Consequence

ALS2
NM_020919.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.02

Publications

2 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=-0.92).

BP6

Variant 2-201757786-T-C is Benign according to our data. Variant chr2-201757786-T-C is described in ClinVar as [Benign]. Clinvar id is 261365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4 link	c.1114-27A>G		intron_variant	Intron 4 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.1114-27A>G		intron_variant	Intron 4 of 33	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.169

AC:

25719

AN:

151986

Hom.:

2498

Cov.:

show subpopulations

Gnomad AFR

AF:

0.186

Gnomad AMI

AF:

0.0724

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.405

Gnomad SAS

AF:

0.336

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.161

GnomAD2 exomes

AF:

0.218

AC:

43400

AN:

199222

AF XY:

0.223

show subpopulations

Gnomad AFR exome

AF:

0.229

Gnomad AMR exome

AF:

0.142

Gnomad ASJ exome

AF:

0.183

Gnomad EAS exome

AF:

0.450

Gnomad FIN exome

AF:

0.243

Gnomad NFE exome

AF:

0.164

Gnomad OTH exome

AF:

0.195

GnomAD4 exome

AF:

0.160

AC:

216950

AN:

1352198

Hom.:

20770

Cov.:

AF XY:

0.165

AC XY:

111931

AN XY:

676454

show subpopulations

African (AFR)

AF:

0.203

AC:

6180

AN:

30400

American (AMR)

AF:

0.142

AC:

5973

AN:

41960

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

4454

AN:

25312

East Asian (EAS)

AF:

0.418

AC:

15918

AN:

38062

South Asian (SAS)

AF:

0.324

AC:

26769

AN:

82660

European-Finnish (FIN)

AF:

0.211

AC:

8314

AN:

39372

Middle Eastern (MID)

AF:

0.172

AC:

929

AN:

5400

European-Non Finnish (NFE)

AF:

0.134

AC:

138233

AN:

1032316

Other (OTH)

AF:

0.179

AC:

10180

AN:

56716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

8995

17989

26984

35978

44973

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.169

AC:

25737

AN:

152104

Hom.:

2498

Cov.:

AF XY:

0.175

AC XY:

13027

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.186

AC:

7713

AN:

41482

American (AMR)

AF:

0.121

AC:

1853

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

597

AN:

3468

East Asian (EAS)

AF:

0.405

AC:

2096

AN:

5180

South Asian (SAS)

AF:

0.337

AC:

1623

AN:

4822

European-Finnish (FIN)

AF:

0.223

AC:

2358

AN:

10576

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.133

AC:

9048

AN:

67996

Other (OTH)

AF:

0.161

AC:

339

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1082

2163

3245

4326

5408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.161

Hom.:

556

Bravo

AF:

0.163

Asia WGS

AF:

0.370

AC:

1284

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 06, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.086

(source)

DANN

Benign

0.42

PhyloP100

-1.0

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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NM_020919.4:c.1114-27A>G

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