2-201761714-T-C

Variant names:

Variant summary

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

The NM_020919.4(ALS2):c.280A>G(p.Ile94Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,613,992 control chromosomes in the GnomAD database, including 740 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 97 hom., cov: 32)

Exomes 𝑓: 0.028 ( 643 hom. )

Consequence

ALS2
NM_020919.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.888

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 (MetaRNN=0.0023296773).

BP6

Variant 2-201761714-T-C is Benign according to our data. Variant chr2-201761714-T-C is described in ClinVar as [Benign]. Clinvar id is 261370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201761714-T-C is described in Lovd as [Benign]. Variant chr2-201761714-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0333 (5069/152108) while in subpopulation AFR AF= 0.0518 (2148/41482). AF 95% confidence interval is 0.05. There are 97 homozygotes in gnomad4. There are 2412 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 97 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4 link	c.280A>G	p.Ile94Val	missense_variant	Exon 4 of 34	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.280A>G	p.Ile94Val	missense_variant	Exon 4 of 34	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.0333

AC:

5059

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0519

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0240

Gnomad ASJ

AF:

0.0493

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.0244

Gnomad FIN

AF:

0.0241

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0283

Gnomad OTH

AF:

0.0259

GnomAD3 exomes

AF:

0.0251

AC:

6235

AN:

248818

Hom.:

113

AF XY:

0.0250

AC XY:

3382

AN XY:

135058

show subpopulations

Gnomad AFR exome

AF:

0.0539

Gnomad AMR exome

AF:

0.0145

Gnomad ASJ exome

AF:

0.0480

Gnomad EAS exome

AF:

0.000556

Gnomad SAS exome

AF:

0.0261

Gnomad FIN exome

AF:

0.0220

Gnomad NFE exome

AF:

0.0263

Gnomad OTH exome

AF:

0.0286

GnomAD4 exome

AF:

0.0284

AC:

41510

AN:

1461884

Hom.:

643

Cov.:

AF XY:

0.0280

AC XY:

20344

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0498

Gnomad4 AMR exome

AF:

0.0148

Gnomad4 ASJ exome

AF:

0.0488

Gnomad4 EAS exome

AF:

0.000453

Gnomad4 SAS exome

AF:

0.0257

Gnomad4 FIN exome

AF:

0.0224

Gnomad4 NFE exome

AF:

0.0294

Gnomad4 OTH exome

AF:

0.0279

GnomAD4 genome

AF:

0.0333

AC:

5069

AN:

152108

Hom.:

Cov.:

AF XY:

0.0324

AC XY:

2412

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0518

Gnomad4 AMR

AF:

0.0240

Gnomad4 ASJ

AF:

0.0493

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.0243

Gnomad4 FIN

AF:

0.0241

Gnomad4 NFE

AF:

0.0283

Gnomad4 OTH

AF:

0.0304

Alfa

AF:

0.0285

Hom.:

141

Bravo

AF:

0.0330

TwinsUK

AF:

0.0329

AC:

122

ALSPAC

AF:

0.0306

AC:

118

ESP6500AA

AF:

0.0501

AC:

198

ESP6500EA

AF:

0.0256

AC:

213

ExAC

AF:

0.0249

AC:

3008

Asia WGS

AF:

0.0420

AC:

146

AN:

3478

EpiCase

AF:

0.0260

EpiControl

AF:

0.0249

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Aug 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28430856, 18810511, 14676054, 25588603) -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Infantile-onset ascending hereditary spastic paralysis

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amyotrophic lateral sclerosis type 2, juvenile

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

ALS2-related disorder

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary spastic paraplegia

Benign:1

Nov 23, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.090

T;.;.;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.46

T;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.15

N;N;.;.

PrimateAI

Benign

0.39

PROVEAN

Benign

0.28

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;.;.

Polyphen

0.0

B;B;.;.

Vest4

0.020

MPC

0.19

ClinPred

0.00064

GERP RS

2.9

Varity_R

0.014

gMVP

0.28

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