chr2-201727791-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.2842-16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00534 in 1,551,238 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 169 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 185 hom. )

Consequence

ALS2
NM_020919.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.46

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=-0.9).

BP6

Variant 2-201727791-C-T is Benign according to our data. Variant chr2-201727791-C-T is described in ClinVar as Benign. ClinVar VariationId is 261372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4 link	c.2842-16G>A		intron_variant	Intron 15 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.2842-16G>A		intron_variant	Intron 15 of 33	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.0276

AC:

4201

AN:

152126

Hom.:

169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0955

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.00630

AC:

974

AN:

154538

AF XY:

0.00512

show subpopulations

Gnomad AFR exome

AF:

0.0999

Gnomad AMR exome

AF:

0.00437

Gnomad ASJ exome

AF:

0.00176

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000450

Gnomad OTH exome

AF:

0.00460

GnomAD4 exome

AF:

0.00292

AC:

4087

AN:

1398994

Hom.:

185

Cov.:

AF XY:

0.00265

AC XY:

1829

AN XY:

690058

show subpopulations

African (AFR)

AF:

0.104

AC:

3269

AN:

31568

American (AMR)

AF:

0.00555

AC:

198

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00171

AC:

AN:

25180

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35730

South Asian (SAS)

AF:

0.000202

AC:

AN:

79226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49284

Middle Eastern (MID)

AF:

0.00441

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.000192

AC:

207

AN:

1078642

Other (OTH)

AF:

0.00566

AC:

328

AN:

57986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

197

394

591

788

985

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.0276

AC:

4204

AN:

152244

Hom.:

169

Cov.:

AF XY:

0.0265

AC XY:

1975

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0953

AC:

3956

AN:

41524

American (AMR)

AF:

0.0107

AC:

163

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68026

Other (OTH)

AF:

0.0170

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

194

388

583

777

971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0139

Hom.:

Bravo

AF:

0.0316

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 18, 2018

GeneDx

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

-0.90

CADD

Benign

0.053

(source)

DANN

Benign

0.89

PhyloP100

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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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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