rs3219170

chr2-201705509-A-Gchr2-201705509-A-T

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.4581-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 1,485,640 control chromosomes in the GnomAD database, including 631,949 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61068 hom., cov: 32)
  • Exomes 𝑓: 0.92 (570881 hom.)
• Consequence: ALS2 NM_020919.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.198

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=-0.9).
• BP6: Variant 2-201705509-A-G is Benign according to our data. Variant chr2-201705509-A-G is described in ClinVar as [Benign]. Clinvar id is 261379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALS2	NM_020919.4	c.4581-48T>C		intron_variant		ENST00000264276.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALS2	ENST00000264276.11	c.4581-48T>C		intron_variant		1	NM_020919.4	P4

Frequencies

GnomAD3 genomes AF: 0.894 AC: 136002 AN: 152088 Hom.: 61021 Cov.: 32

Gnomad AFR AF: 0.819

Gnomad AMI AF: 0.981

Gnomad AMR AF: 0.882

Gnomad ASJ AF: 0.914

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.959

Gnomad FIN AF: 0.961

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.919

Gnomad OTH AF: 0.880

GnomAD3 exomes AF: 0.923 AC: 221992 AN: 240488 Hom.: 102622 AF XY: 0.928 AC XY: 121188 AN XY: 130660

Gnomad AFR exome AF: 0.821

Gnomad AMR exome AF: 0.893

Gnomad ASJ exome AF: 0.916

Gnomad EAS exome AF: 0.986

Gnomad SAS exome AF: 0.960

Gnomad FIN exome AF: 0.954

Gnomad NFE exome AF: 0.921

Gnomad OTH exome AF: 0.920

GnomAD4 exome AF: 0.925 AC: 1233347 AN: 1333434 Hom.: 570881 Cov.: 19 AF XY: 0.927 AC XY: 621142 AN XY: 670362

Gnomad4 AFR exome AF: 0.825

Gnomad4 AMR exome AF: 0.890

Gnomad4 ASJ exome AF: 0.914

Gnomad4 EAS exome AF: 0.991

Gnomad4 SAS exome AF: 0.959

Gnomad4 FIN exome AF: 0.954

Gnomad4 NFE exome AF: 0.923

Gnomad4 OTH exome AF: 0.922

GnomAD4 genome AF: 0.894 AC: 136108 AN: 152206 Hom.: 61068 Cov.: 32 AF XY: 0.898 AC XY: 66792 AN XY: 74406

Gnomad4 AFR AF: 0.819

Gnomad4 AMR AF: 0.882

Gnomad4 ASJ AF: 0.914

Gnomad4 EAS AF: 0.985

Gnomad4 SAS AF: 0.959

Gnomad4 FIN AF: 0.961

Gnomad4 NFE AF: 0.919

Gnomad4 OTH AF: 0.880

Alfa AF: 0.904 Hom.: 12044

Bravo AF: 0.885

Asia WGS AF: 0.958 AC: 3327 AN: 3474

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

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- -

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	-0.90
Cadd	Benign	4.1
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3219170; hg19: chr2-202570232;