2-201733390-C-T

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.2466G>A(p.Val822Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 1,612,934 control chromosomes in the GnomAD database, including 274,463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 19749 hom., cov: 32)

Exomes 𝑓: 0.58 ( 254714 hom. )

Consequence

ALS2
ENST00000264276.11 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0570

Publications

25 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=-0.48).

BP6

Variant 2-201733390-C-T is Benign according to our data. Variant chr2-201733390-C-T is described in ClinVar as Benign. ClinVar VariationId is 261368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.057 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.607 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.2466G>A	p.Val822Val	synonymous	Exon 13 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.2466G>A	p.Val822Val	synonymous	Exon 13 of 34	NP_001397904.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALS2	ENST00000264276.11	TSL:1 MANE Select	c.2466G>A	p.Val822Val	synonymous	Exon 13 of 34	ENSP00000264276.6
ALS2	ENST00000482789.6	TSL:1	n.2808G>A		non_coding_transcript_exon	Exon 13 of 13
ALS2	ENST00000482891.6	TSL:1	n.2808G>A		non_coding_transcript_exon	Exon 13 of 22

Frequencies

GnomAD3 genomes

AF:

0.468

AC:

71090

AN:

151862

Hom.:

19747

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.674

Gnomad AMR

AF:

0.604

Gnomad ASJ

AF:

0.557

Gnomad EAS

AF:

0.355

Gnomad SAS

AF:

0.393

Gnomad FIN

AF:

0.564

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.612

Gnomad OTH

AF:

0.486

GnomAD2 exomes

AF:

0.539

AC:

134219

AN:

248966

AF XY:

0.538

show subpopulations

Gnomad AFR exome

AF:

0.153

Gnomad AMR exome

AF:

0.666

Gnomad ASJ exome

AF:

0.548

Gnomad EAS exome

AF:

0.348

Gnomad FIN exome

AF:

0.577

Gnomad NFE exome

AF:

0.613

Gnomad OTH exome

AF:

0.558

GnomAD4 exome

AF:

0.582

AC:

850622

AN:

1460954

Hom.:

254714

Cov.:

AF XY:

0.579

AC XY:

420628

AN XY:

726788

show subpopulations

African (AFR)

AF:

0.153

AC:

5104

AN:

33466

American (AMR)

AF:

0.652

AC:

29130

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.548

AC:

14312

AN:

26116

East Asian (EAS)

AF:

0.355

AC:

14074

AN:

39616

South Asian (SAS)

AF:

0.408

AC:

35156

AN:

86228

European-Finnish (FIN)

AF:

0.579

AC:

30847

AN:

53294

Middle Eastern (MID)

AF:

0.529

AC:

3046

AN:

5762

European-Non Finnish (NFE)

AF:

0.617

AC:

686086

AN:

1111404

Other (OTH)

AF:

0.545

AC:

32867

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

17578

35156

52733

70311

87889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18168

36336

54504

72672

90840

<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:

0.468

AC:

71089

AN:

151980

Hom.:

19749

Cov.:

AF XY:

0.467

AC XY:

34678

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.166

AC:

6889

AN:

41446

American (AMR)

AF:

0.604

AC:

9221

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.557

AC:

1934

AN:

3470

East Asian (EAS)

AF:

0.356

AC:

1838

AN:

5170

South Asian (SAS)

AF:

0.392

AC:

1891

AN:

4820

European-Finnish (FIN)

AF:

0.564

AC:

5929

AN:

10510

Middle Eastern (MID)

AF:

0.517

AC:

151

AN:

292

European-Non Finnish (NFE)

AF:

0.612

AC:

41604

AN:

67972

Other (OTH)

AF:

0.482

AC:

1019

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1662

3324

4986

6648

8310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

620

1240

1860

2480

3100

<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:

0.567

Hom.:

40248

Bravo

AF:

0.460

Asia WGS

AF:

0.318

AC:

1108

AN:

3476

EpiCase

AF:

0.614

EpiControl

AF:

0.610

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

-0.48

CADD

Benign

4.6

(source)

DANN

Benign

0.68

PhyloP100

-0.057

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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