chr2-201706839-C-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.4580+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,613,320 control chromosomes in the GnomAD database, including 26,300 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2673 hom., cov: 31)

Exomes 𝑓: 0.16 ( 23627 hom. )

Consequence

ALS2
NM_020919.4 splice_region, intron

Scores

Splicing: ADA: 0.00001254

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -0.271

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
juvenile primary lateral sclerosis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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=-0.87).

BP6

Variant 2-201706839-C-T is Benign according to our data. Variant chr2-201706839-C-T is described in ClinVar as Benign. ClinVar VariationId is 261378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020919.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	NM_020919.4	MANE Select	c.4580+7G>A		splice_region intron	N/A	NP_065970.2
	ALS2	NM_001410975.1		c.4577+7G>A		splice_region intron	N/A	NP_001397904.1	A0A7P0T8F3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ALS2	ENST00000264276.11	TSL:1 MANE Select	c.4580+7G>A	splice_region intron	N/A	ENSP00000264276.6	Q96Q42-1
ALS2	ENST00000680497.1		c.4682+7G>A	splice_region intron	N/A	ENSP00000505954.1	A0A7P0Z4F3
ALS2	ENST00000905985.1		c.4673+7G>A	splice_region intron	N/A	ENSP00000576044.1

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26896

AN:

151858

Hom.:

2670

Cov.:

show subpopulations

Gnomad AFR

AF:

0.191

Gnomad AMI

AF:

0.0725

Gnomad AMR

AF:

0.133

Gnomad ASJ

AF:

0.194

Gnomad EAS

AF:

0.391

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.141

Gnomad OTH

AF:

0.169

GnomAD2 exomes

AF:

0.204

AC:

50808

AN:

249208

AF XY:

0.210

show subpopulations

Gnomad AFR exome

AF:

0.196

Gnomad AMR exome

AF:

0.137

Gnomad ASJ exome

AF:

0.194

Gnomad EAS exome

AF:

0.404

Gnomad FIN exome

AF:

0.222

Gnomad NFE exome

AF:

0.149

Gnomad OTH exome

AF:

0.188

GnomAD4 exome

AF:

0.165

AC:

241076

AN:

1461344

Hom.:

23627

Cov.:

AF XY:

0.171

AC XY:

123975

AN XY:

727006

show subpopulations

African (AFR)

AF:

0.201

AC:

6742

AN:

33474

American (AMR)

AF:

0.142

AC:

6338

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.193

AC:

5039

AN:

26126

East Asian (EAS)

AF:

0.396

AC:

15706

AN:

39676

South Asian (SAS)

AF:

0.350

AC:

30150

AN:

86238

European-Finnish (FIN)

AF:

0.217

AC:

11589

AN:

53370

Middle Eastern (MID)

AF:

0.173

AC:

995

AN:

5766

European-Non Finnish (NFE)

AF:

0.138

AC:

153350

AN:

1111596

Other (OTH)

AF:

0.185

AC:

11167

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

9597

19194

28791

38388

47985

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5800

11600

17400

23200

29000

<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:

0.177

AC:

26925

AN:

151976

Hom.:

2673

Cov.:

AF XY:

0.184

AC XY:

13634

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.191

AC:

7933

AN:

41448

American (AMR)

AF:

0.133

AC:

2033

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.194

AC:

675

AN:

3472

East Asian (EAS)

AF:

0.391

AC:

2016

AN:

5160

South Asian (SAS)

AF:

0.366

AC:

1759

AN:

4808

European-Finnish (FIN)

AF:

0.231

AC:

2437

AN:

10542

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.141

AC:

9597

AN:

67974

Other (OTH)

AF:

0.172

AC:

361

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1072

2144

3215

4287

5359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

318

636

954

1272

1590

<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:

0.130

Hom.:

557

Bravo

AF:

0.169

Asia WGS

AF:

0.385

AC:

1334

AN:

3478

EpiCase

AF:

0.138

EpiControl

AF:

0.148

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

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

-0.87

CADD

Benign

0.24

(source)

DANN

Benign

0.44

PhyloP100

-0.27

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000013

dbscSNV1_RF

Benign

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over