rs190369242
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_020919.4(ALS2):āc.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
Consequence
NM_020919.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000973 AC: 148AN: 152130Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00108 AC: 260AN: 240124Hom.: 1 AF XY: 0.00121 AC XY: 159AN XY: 131076
GnomAD4 exome AF: 0.00146 AC: 2124AN: 1451118Hom.: 3 Cov.: 31 AF XY: 0.00149 AC XY: 1079AN XY: 722482
GnomAD4 genome AF: 0.000972 AC: 148AN: 152248Hom.: 1 Cov.: 32 AF XY: 0.000954 AC XY: 71AN XY: 74434
ClinVar
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | ALS2: BP4, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 06, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2019 | This 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 submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | May 12, 2021 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 01, 2023 | Variant 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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | - - |
Amyotrophic lateral sclerosis type 2, juvenile Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This 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 submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at