rs762209905
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_025137.4(SPG11):āc.6737T>Cā(p.Ile2246Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,714 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2246M) has been classified as Uncertain significance.
Frequency
Consequence
NM_025137.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.6737T>C | p.Ile2246Thr | missense_variant | 36/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.6737T>C | p.Ile2246Thr | missense_variant | 36/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151882Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251462Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135912
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461832Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8AN XY: 727218
GnomAD4 genome AF: 0.0000198 AC: 3AN: 151882Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74140
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2246 of the SPG11 protein (p.Ile2246Thr). This variant is present in population databases (rs762209905, gnomAD 0.004%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 33589474). ClinVar contains an entry for this variant (Variation ID: 573065). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at