Genetic Variant ALS2:c.3248+50G>A (chr2-201726434-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020919.4(ALS2):c.3248+50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,468,126 control chromosomes in the GnomAD database, including 267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 24 hom., cov: 32)

Exomes 𝑓: 0.017 ( 243 hom. )

Consequence

ALS2
NM_020919.4 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.106

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 2-201726434-C-T is Benign according to our data. Variant chr2-201726434-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0136 (2066/152260) while in subpopulation NFE AF= 0.0184 (1252/68024). AF 95% confidence interval is 0.0176. There are 24 homozygotes in gnomad4. There are 1034 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4 link	c.3248+50G>A		intron_variant	Intron 19 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.3248+50G>A		intron_variant	Intron 19 of 33	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2069

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00382

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.0372

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.0216

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0184

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0156

AC:

3871

AN:

248548

Hom.:

AF XY:

0.0158

AC XY:

2137

AN XY:

134892

show subpopulations

Gnomad AFR exome

AF:

0.00311

Gnomad AMR exome

AF:

0.00920

Gnomad ASJ exome

AF:

0.0404

Gnomad EAS exome

AF:

0.0000558

Gnomad SAS exome

AF:

0.00475

Gnomad FIN exome

AF:

0.0216

Gnomad NFE exome

AF:

0.0209

Gnomad OTH exome

AF:

0.0233

GnomAD4 exome

AF:

0.0172

AC:

22693

AN:

1315866

Hom.:

243

Cov.:

AF XY:

0.0171

AC XY:

11336

AN XY:

662728

show subpopulations

Gnomad4 AFR exome

AF:

0.00322

Gnomad4 AMR exome

AF:

0.00921

Gnomad4 ASJ exome

AF:

0.0390

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.00505

Gnomad4 FIN exome

AF:

0.0238

Gnomad4 NFE exome

AF:

0.0189

Gnomad4 OTH exome

AF:

0.0161

GnomAD4 genome

AF:

0.0136

AC:

2066

AN:

152260

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1034

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00381

Gnomad4 AMR

AF:

0.0103

Gnomad4 ASJ

AF:

0.0372

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.0216

Gnomad4 NFE

AF:

0.0184

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0115

Hom.:

Bravo

AF:

0.0130

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

5.3

DANN

Benign

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over