rs3219167

Positions:

• chr2-201715647-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020919.4(ALS2):​c.4004+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.83 in 1,613,194 control chromosomes in the GnomAD database, including 556,568 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (50739 hom., cov: 32)
  • Exomes 𝑓: 0.83 (505829 hom.)
• Consequence: ALS2 NM_020919.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.859

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-201715647-G-A is Benign according to our data. Variant chr2-201715647-G-A is described in ClinVar as [Benign]. Clinvar id is 261375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALS2	NM_020919.4	c.4004+25C>T		intron_variant		ENST00000264276.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALS2	ENST00000264276.11	c.4004+25C>T		intron_variant		1	NM_020919.4	P4

Frequencies

GnomAD3 genomes AF: 0.816 AC: 124110 AN: 152064 Hom.: 50695 Cov.: 32

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.841

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.807

GnomAD3 exomes AF: 0.831 AC: 205194 AN: 246858 Hom.: 85330 AF XY: 0.833 AC XY: 111727 AN XY: 134158

Gnomad AFR exome AF: 0.782

Gnomad AMR exome AF: 0.858

Gnomad ASJ exome AF: 0.839

Gnomad EAS exome AF: 0.749

Gnomad SAS exome AF: 0.842

Gnomad FIN exome AF: 0.856

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.832

GnomAD4 exome AF: 0.832 AC: 1214904 AN: 1461012 Hom.: 505829 Cov.: 41 AF XY: 0.832 AC XY: 605058 AN XY: 726826

Gnomad4 AFR exome AF: 0.785

Gnomad4 AMR exome AF: 0.853

Gnomad4 ASJ exome AF: 0.837

Gnomad4 EAS exome AF: 0.748

Gnomad4 SAS exome AF: 0.842

Gnomad4 FIN exome AF: 0.854

Gnomad4 NFE exome AF: 0.833

Gnomad4 OTH exome AF: 0.828

GnomAD4 genome AF: 0.816 AC: 124209 AN: 152182 Hom.: 50739 Cov.: 32 AF XY: 0.817 AC XY: 60810 AN XY: 74410

Gnomad4 AFR AF: 0.780

Gnomad4 AMR AF: 0.834

Gnomad4 ASJ AF: 0.844

Gnomad4 EAS AF: 0.747

Gnomad4 SAS AF: 0.841

Gnomad4 FIN AF: 0.856

Gnomad4 NFE AF: 0.831

Gnomad4 OTH AF: 0.808

Alfa AF: 0.831 Hom.: 54052

Bravo AF: 0.812

Asia WGS AF: 0.788 AC: 2739 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Infantile-onset ascending hereditary spastic paralysis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Juvenile primary lateral sclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Amyotrophic lateral sclerosis type 2, juvenile Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.45
DANN	Benign	0.50

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

LitVar

Other links and lift over

dbSNP: rs3219167; hg19: chr2-202580370;