Genetic Variant NM_020919.4:c.4004+25C>T (chr2-201715647-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.859

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
ALS2	NM_020919.4 link	c.4004+25C>T		intron_variant	Intron 25 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.4004+25C>T		intron_variant	Intron 25 of 33	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.816

AC:

124110

AN:

152064

Hom.:

50695

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.832

AC XY:

605058

AN XY:

726826

show subpopulations

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.:

AF XY:

0.817

AC XY:

60810

AN XY:

74410

show subpopulations

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juvenile primary lateral sclerosis

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amyotrophic lateral sclerosis type 2, juvenile

Benign:1

Jul 14, 2021

Genome-Nilou Lab

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

-0.81

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

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