rs201721414
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_025137.4(SPG11):c.6878G>A(p.Arg2293Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,613,878 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2293W) has been classified as Likely benign.
Frequency
Consequence
NM_025137.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.6878G>A | p.Arg2293Gln | missense_variant | 38/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.6878G>A | p.Arg2293Gln | missense_variant | 38/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152088Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000115 AC: 29AN: 251124Hom.: 0 AF XY: 0.0000958 AC XY: 13AN XY: 135768
GnomAD4 exome AF: 0.000200 AC: 293AN: 1461672Hom.: 1 Cov.: 32 AF XY: 0.000198 AC XY: 144AN XY: 727136
GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74402
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2021 | Reported previously in a patient with Parkinson's disease, however further clinical information was not provided (Ghani et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29119460, 25174650) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | SPG11: PM2 - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Hereditary spastic paraplegia 11 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 15, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2293 of the SPG11 protein (p.Arg2293Gln). This variant is present in population databases (rs201721414, gnomAD 0.04%). This missense change has been observed in individual(s) with Parkinson's disease (PMID: 25174650). This variant is also known as p.Arg2180Gln. ClinVar contains an entry for this variant (Variation ID: 522343). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Oct 09, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 11, 2024 | Variant summary: SPG11 c.6878G>A (p.Arg2293Gln) results in a conservative amino acid change located in the Spatacsin, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251124 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (0.00012 vs 0.0011), allowing no conclusion about variant significance. c.6878G>A has been reported in the literature in an individual affected with Parkinson's disease (Ghani_2016). This report does not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia, Type 11. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25174650). ClinVar contains an entry for this variant (Variation ID: 522343). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2023 | The c.6878G>A (p.R2293Q) alteration is located in exon 38 (coding exon 38) of the SPG11 gene. This alteration results from a G to A substitution at nucleotide position 6878, causing the arginine (R) at amino acid position 2293 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Amyotrophic lateral sclerosis type 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Charcot-Marie-Tooth disease axonal type 2X Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at