chr19-45494235-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_005619.5(RTN2):c.745G>A(p.Glu249Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000875 in 1,612,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. E249Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_005619.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RTN2 | NM_005619.5 | c.745G>A | p.Glu249Lys | missense_variant | 4/11 | ENST00000245923.9 | |
RTN2 | NM_206900.3 | c.745G>A | p.Glu249Lys | missense_variant | 4/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RTN2 | ENST00000245923.9 | c.745G>A | p.Glu249Lys | missense_variant | 4/11 | 1 | NM_005619.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249532Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134902
GnomAD4 exome AF: 0.0000931 AC: 136AN: 1460148Hom.: 0 Cov.: 31 AF XY: 0.0000936 AC XY: 68AN XY: 726392
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74318
ClinVar
Submissions by phenotype
Spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2022 | 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. 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 964495). This variant has not been reported in the literature in individuals affected with RTN2-related conditions. This variant is present in population databases (rs761286207, gnomAD 0.006%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 249 of the RTN2 protein (p.Glu249Lys). - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 17, 2024 | The c.745G>A (p.E249K) alteration is located in exon 4 (coding exon 4) of the RTN2 gene. This alteration results from a G to A substitution at nucleotide position 745, causing the glutamic acid (E) at amino acid position 249 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 02, 2023 | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at