Genetic Variant ALS2:p.Arg1341Pro (chr2-201711091-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020919.4(ALS2):c.4022G>C(p.Arg1341Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,738 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1341H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ALS2
NM_020919.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.24

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

ALS2-related motor neuron disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
amyotrophic lateral sclerosis type 2, juvenile
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
infantile-onset ascending hereditary spastic paralysis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
juvenile primary lateral sclerosis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
juvenile amyotrophic lateral sclerosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ALS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4 link	c.4022G>C	p.Arg1341Pro	missense_variant	Exon 26 of 34	ENST00000264276.11	NP_065970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11 link	c.4022G>C	p.Arg1341Pro	missense_variant	Exon 26 of 34	1	NM_020919.4	ENSP00000264276.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1450738

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33244

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39574

South Asian (SAS)

AF:

0.00

AC:

AN:

86040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53200

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102128

Other (OTH)

AF:

0.00

AC:

AN:

60036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.058

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.4

PhyloP100

7.2

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.33

Sift

Uncertain

0.016

Sift4G

Uncertain

0.0060

Polyphen

0.90

Vest4

0.83

MutPred

0.33

Gain of glycosylation at R1341 (P = 0.0288);

MVP

0.80

MPC

0.37

ClinPred

0.99

GERP RS

5.8

Varity_R

0.61

gMVP

0.73

Mutation Taster

=46/54

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over