2-201711098-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000264276.11(ALS2):c.4015C>T(p.Leu1339Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 1,597,622 control chromosomes in the GnomAD database, including 679,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.89 ( 61052 hom., cov: 31)

Exomes 𝑓: 0.92 ( 618575 hom. )

Consequence

ALS2
ENST00000264276.11 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -2.01

Publications

30 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 2-201711098-G-A is Benign according to our data. Variant chr2-201711098-G-A is described in ClinVar as Benign. ClinVar VariationId is 261377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.01 with no splicing effect.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000264276.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	NM_020919.4	MANE Select	c.4015C>T	p.Leu1339Leu	synonymous	Exon 26 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.4012C>T	p.Leu1338Leu	synonymous	Exon 26 of 34	NP_001397904.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALS2	ENST00000264276.11	TSL:1 MANE Select	c.4015C>T	p.Leu1339Leu	synonymous	Exon 26 of 34	ENSP00000264276.6
ALS2	ENST00000680497.1		c.4117C>T	p.Leu1373Leu	synonymous	Exon 26 of 34	ENSP00000505954.1
ALS2	ENST00000679516.1		c.4015C>T	p.Leu1339Leu	synonymous	Exon 25 of 33	ENSP00000505187.1

Frequencies

GnomAD3 genomes

AF:

0.894

AC:

135975

AN:

152064

Hom.:

61006

Cov.:

show subpopulations

Gnomad AFR

AF:

0.818

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:

0.920

Gnomad OTH

AF:

0.879

GnomAD2 exomes

AF:

0.923

AC:

229663

AN:

248828

AF XY:

0.927

show subpopulations

Gnomad AFR exome

AF:

0.819

Gnomad AMR exome

AF:

0.892

Gnomad ASJ exome

AF:

0.916

Gnomad EAS exome

AF:

0.986

Gnomad FIN exome

AF:

0.955

Gnomad NFE exome

AF:

0.921

Gnomad OTH exome

AF:

0.919

GnomAD4 exome

AF:

0.925

AC:

1336609

AN:

1445440

Hom.:

618575

Cov.:

AF XY:

0.926

AC XY:

667121

AN XY:

720206

show subpopulations

African (AFR)

AF:

0.823

AC:

27258

AN:

33134

American (AMR)

AF:

0.889

AC:

39746

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.915

AC:

23813

AN:

26032

East Asian (EAS)

AF:

0.991

AC:

39165

AN:

39538

South Asian (SAS)

AF:

0.958

AC:

82340

AN:

85938

European-Finnish (FIN)

AF:

0.954

AC:

50643

AN:

53082

Middle Eastern (MID)

AF:

0.904

AC:

5200

AN:

5752

European-Non Finnish (NFE)

AF:

0.923

AC:

1013288

AN:

1097416

Other (OTH)

AF:

0.921

AC:

55156

AN:

59858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

4499

8998

13497

17996

22495

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21150

42300

63450

84600

105750

<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:

136079

AN:

152182

Hom.:

61052

Cov.:

AF XY:

0.898

AC XY:

66780

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.818

AC:

33964

AN:

41506

American (AMR)

AF:

0.882

AC:

13487

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.914

AC:

3173

AN:

3472

East Asian (EAS)

AF:

0.985

AC:

5098

AN:

5178

South Asian (SAS)

AF:

0.959

AC:

4612

AN:

4810

European-Finnish (FIN)

AF:

0.961

AC:

10186

AN:

10600

Middle Eastern (MID)

AF:

0.878

AC:

258

AN:

294

European-Non Finnish (NFE)

AF:

0.920

AC:

62551

AN:

68018

Other (OTH)

AF:

0.880

AC:

1855

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

730

1460

2191

2921

3651

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:

0.909

Hom.:

101676

Bravo

AF:

0.885

Asia WGS

AF:

0.957

AC:

3329

AN:

3478

EpiCase

AF:

0.915

EpiControl

AF:

0.918

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (3)

Amyotrophic lateral sclerosis type 2, juvenile (2)

Infantile-onset ascending hereditary spastic paralysis (2)

ALS2-related disorder (1)

Juvenile primary lateral sclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.28

(source)

DANN

Benign

0.61

PhyloP100

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over