chr19-45493254-A-AG
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1PP5BS2
The NM_005619.5(RTN2):c.938dupC(p.Thr314fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
RTN2
NM_005619.5 frameshift
NM_005619.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.283
Genes affected
RTN2 (HGNC:10468): (reticulon 2) This gene belongs to the family of reticulon encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. Reticulon proteins also play an important role in the replication of positive-strand RNA (ssRNA) viruses. Mutations at this locus have been associated with autosomal dominant spastic paraplegia-12. [provided by RefSeq, Aug 2020]
PPM1N (HGNC:26845): (protein phosphatase, Mg2+/Mn2+ dependent 1N (putative)) Predicted to enable metal ion binding activity and protein serine/threonine phosphatase activity. Predicted to be involved in negative regulation of I-kappaB kinase/NF-kappaB signaling and positive regulation of canonical Wnt signaling pathway. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 19-45493254-A-AG is Pathogenic according to our data. Variant chr19-45493254-A-AG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548603.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.
BS2
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RTN2 | NM_005619.5 | c.938dupC | p.Thr314fs | frameshift_variant | 5/11 | ENST00000245923.9 | NP_005610.1 | |
RTN2 | NM_206900.3 | c.814+911dupC | intron_variant | NP_996783.1 | ||||
RTN2 | NM_206901.3 | c.-83dupC | upstream_gene_variant | NP_996784.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RTN2 | ENST00000245923.9 | c.938dupC | p.Thr314fs | frameshift_variant | 5/11 | 1 | NM_005619.5 | ENSP00000245923.3 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152110Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461048Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28AN XY: 726824
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152110Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74304
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 12 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 15, 2022 | Variant summary: RTN2 c.938dupC (p.Thr314TyrfsX31) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.1167C>A [p.Cys389Ter]). The variant allele was found at a frequency of 4.4e-05 in 248550 control chromosomes (gnomAD). To our knowledge, no occurrence of c.938dupC in individuals affected with Spastic Paraplegia 12 and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as of uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 14, 2022 | This sequence change creates a premature translational stop signal (p.Thr314Tyrfs*31) in the RTN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RTN2 are known to be pathogenic (PMID: 22232211, 27165006). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RTN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 548603). For these reasons, this variant has been classified as Pathogenic. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at