2-201711091-C-T

Position:

chr2-201711091-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP5_Strong

The NM_020919.4(ALS2):c.4022G>A(p.Arg1341His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,602,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

ALS2
NM_020919.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:3

Conservation

PhyloP100: 7.24

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:

ALS2 (HGNC:):

ALS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-201711091-C-T is Pathogenic according to our data. Variant chr2-201711091-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 374111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALS2	NM_020919.4 linkuse as main transcript	c.4022G>A	p.Arg1341His	missense_variant	26/34	ENST00000264276.11	NP_065970.2	Q96Q42-1A8K4R4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11 linkuse as main transcript	c.4022G>A	p.Arg1341His	missense_variant	26/34	1	NM_020919.4	ENSP00000264276.6		Q96Q42-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248822

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135024

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000131

AC:

AN:

1450734

Hom.:

Cov.:

AF XY:

0.00000831

AC XY:

AN XY:

722310

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000136

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 2, juvenile

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Likely pathogenic. -

Peripheral axonal neuropathy

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 12, 2015

- -

Infantile-onset ascending hereditary spastic paralysis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 07, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1341 of the ALS2 protein (p.Arg1341His). This variant is present in population databases (rs761291489, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ALS2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 374111). -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 18, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 09, 2024

PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.57

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.3

REVEL

Benign

0.26

Sift

Benign

0.051

Sift4G

Benign

0.079

Polyphen

0.95

Vest4

0.71

MutPred

0.38

Loss of solvent accessibility (P = 0.0352);

MVP

0.78

MPC

0.34

ClinPred

0.87

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.087

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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