rs147284131

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_020919.4(ALS2):​c.1578A>G​(p.Thr526Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,614,170 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00029 ( 3 hom. )

Consequence

ALS2
NM_020919.4 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.0400
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP6
Variant 2-201754565-T-C is Benign according to our data. Variant chr2-201754565-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 417160.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=1}. Variant chr2-201754565-T-C is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.04 with no splicing effect.
BS1
Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000286 (418/1461864) while in subpopulation MID AF = 0.00867 (50/5768). AF 95% confidence interval is 0.00675. There are 3 homozygotes in GnomAdExome4. There are 226 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position FAILED quality control check.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALS2NM_020919.4 linkc.1578A>G p.Thr526Thr synonymous_variant Exon 6 of 34 ENST00000264276.11 NP_065970.2 Q96Q42-1A8K4R4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALS2ENST00000264276.11 linkc.1578A>G p.Thr526Thr synonymous_variant Exon 6 of 34 1 NM_020919.4 ENSP00000264276.6 Q96Q42-1

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.000957
GnomAD2 exomes
AF:
0.000273
AC:
68
AN:
249500
AF XY:
0.000310
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000580
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000344
Gnomad OTH exome
AF:
0.000660
GnomAD4 exome
AF:
0.000286
AC:
418
AN:
1461864
Hom.:
3
Cov.:
32
AF XY:
0.000311
AC XY:
226
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.000329
AC:
11
AN:
33480
Gnomad4 AMR exome
AF:
0.000581
AC:
26
AN:
44720
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26134
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39700
Gnomad4 SAS exome
AF:
0.000139
AC:
12
AN:
86258
Gnomad4 FIN exome
AF:
0.0000187
AC:
1
AN:
53420
Gnomad4 NFE exome
AF:
0.000256
AC:
285
AN:
1111990
Gnomad4 Remaining exome
AF:
0.000546
AC:
33
AN:
60394
Heterozygous variant carriers
0
25
50
74
99
124
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152306
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.00
AC:
0
AN:
0
Gnomad4 AMR
AF:
0.000196
AC:
0.000196104
AN:
0.000196104
Gnomad4 ASJ
AF:
0.000288
AC:
0.000288184
AN:
0.000288184
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.0000941
AC:
0.0000940911
AN:
0.0000940911
Gnomad4 NFE
AF:
0.000265
AC:
0.000264605
AN:
0.000264605
Gnomad4 OTH
AF:
0.000947
AC:
0.00094697
AN:
0.00094697
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000229
Hom.:
0
Bravo
AF:
0.000257
EpiCase
AF:
0.000545
EpiControl
AF:
0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Jan 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ALS2: BP4, BP7 -

May 03, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 05, 2019
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary spastic paraplegia Uncertain:1
Feb 18, 2021
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Infantile-onset ascending hereditary spastic paralysis Benign:1
Nov 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely 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
-0.51
CADD
Benign
10
DANN
Benign
0.56
Mutation Taster
=58/42
polymorphism

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.

Other links and lift over

dbSNP: rs147284131; hg19: chr2-202619288; API