rs190369242

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020919.4(ALS2):ā€‹c.1115C>Gā€‹(p.Pro372Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,603,366 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00097 ( 1 hom., cov: 32)
Exomes š‘“: 0.0015 ( 3 hom. )

Consequence

ALS2
NM_020919.4 missense, splice_region

Scores

2
17
Splicing: ADA: 0.0004038
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 1.88
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0146540105).
BP6
Variant 2-201757758-G-C is Benign according to our data. Variant chr2-201757758-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241307.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=6, Benign=1}. Variant chr2-201757758-G-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000972 (148/152248) while in subpopulation AMR AF= 0.00164 (25/15290). AF 95% confidence interval is 0.00126. There are 1 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALS2NM_020919.4 linkc.1115C>G p.Pro372Arg missense_variant, splice_region_variant 5/34 ENST00000264276.11 NP_065970.2 Q96Q42-1A8K4R4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALS2ENST00000264276.11 linkc.1115C>G p.Pro372Arg missense_variant, splice_region_variant 5/341 NM_020919.4 ENSP00000264276.6 Q96Q42-1

Frequencies

GnomAD3 genomes
AF:
0.000973
AC:
148
AN:
152130
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00164
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000829
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00150
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00108
AC:
260
AN:
240124
Hom.:
1
AF XY:
0.00121
AC XY:
159
AN XY:
131076
show subpopulations
Gnomad AFR exome
AF:
0.000196
Gnomad AMR exome
AF:
0.000700
Gnomad ASJ exome
AF:
0.000200
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00190
Gnomad FIN exome
AF:
0.0000602
Gnomad NFE exome
AF:
0.00150
Gnomad OTH exome
AF:
0.00118
GnomAD4 exome
AF:
0.00146
AC:
2124
AN:
1451118
Hom.:
3
Cov.:
31
AF XY:
0.00149
AC XY:
1079
AN XY:
722482
show subpopulations
Gnomad4 AFR exome
AF:
0.000420
Gnomad4 AMR exome
AF:
0.000672
Gnomad4 ASJ exome
AF:
0.000268
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00245
Gnomad4 FIN exome
AF:
0.000106
Gnomad4 NFE exome
AF:
0.00155
Gnomad4 OTH exome
AF:
0.00184
GnomAD4 genome
AF:
0.000972
AC:
148
AN:
152248
Hom.:
1
Cov.:
32
AF XY:
0.000954
AC XY:
71
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.00164
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00150
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00132
Hom.:
1
Bravo
AF:
0.000982
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.00234
AC:
9
ESP6500AA
AF:
0.000270
AC:
1
ESP6500EA
AF:
0.00208
AC:
17
ExAC
AF:
0.00107
AC:
129
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00153
EpiControl
AF:
0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2023ALS2: BP4, BS2 -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMay 06, 2022- -
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 13, 2019This variant is associated with the following publications: (PMID: 23881933) -
Juvenile primary lateral sclerosis;C1859807:Amyotrophic lateral sclerosis type 2, juvenile;C2931441:Infantile-onset ascending hereditary spastic paralysis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMay 12, 2021- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 01, 2023Variant summary: ALS2 c.1115C>G (p.Pro372Arg) results in a non-conservative amino acid change in the encoded protein sequence that alters the second nucleotide of exon 5 adjacent to the intron 4 splice acceptor site. Three of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 240124 control chromosomes in the gnomAD database, including 1 homozygote, supporting a benign outcome for a disorder predominantly associated with a juvenile/infantile onset. c.1115C>G has been reported in the literature as a VUS with non-informative genotypes (second allele or zygosity not specified) in cohorts of individuals affected with sporadic or familial ALS (e.g. Kenna_2013, Lamp_2018, Scarlino_2018, Bartoletti-Stella_2021, Blue_2022), as well as in healthy controls (e.g. Kenna_2013, Morgan_2017). These report(s) do not provide unequivocal conclusions about association of the variant with ALS2-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33770234, 34670123, 23881933, 29525178, 28430856, 32397312). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=3) or likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -
Infantile-onset ascending hereditary spastic paralysis Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024- -
Amyotrophic lateral sclerosis type 2, juvenile Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
ALS2-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
21
DANN
Uncertain
0.97
DEOGEN2
Benign
0.10
T
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.13
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.74
T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.015
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.69
N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.56
N
REVEL
Benign
0.12
Sift
Benign
0.53
T
Sift4G
Benign
0.49
T
Polyphen
0.53
P
Vest4
0.55
MVP
0.67
MPC
0.48
ClinPred
0.021
T
GERP RS
4.6
Varity_R
0.049
gMVP
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00040
dbscSNV1_RF
Benign
0.014
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: rs190369242; hg19: chr2-202622481; COSMIC: COSV105081148; COSMIC: COSV105081148; API