rs752707301
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7
The NM_020451.3(SELENON):c.501G>A(p.Pro167Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
SELENON
NM_020451.3 synonymous
NM_020451.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.292
Genes affected
SELENON (HGNC:15999): (selenoprotein N) This gene encodes a glycoprotein that is localized in the endoplasmic reticulum. It plays an important role in cell protection against oxidative stress, and in the regulation of redox-related calcium homeostasis. Mutations in this gene are associated with early onset muscle disorders, referred to as SEPN1-related myopathy. SEPN1-related myopathy consists of 4 autosomal recessive disorders, originally thought to be separate entities: rigid spine muscular dystrophy (RSMD1), the classical form of multiminicore disease, desmin related myopathy with Mallory-body like inclusions, and congenital fiber-type disproportion (CFTD). This protein is a selenoprotein, containing the rare amino acid selenocysteine (Sec). Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. A second stop-codon redefinition element (SRE) adjacent to the UGA codon has been identified in this gene (PMID:15791204). SRE is a phylogenetically conserved stem-loop structure that stimulates readthrough at the UGA codon, and augments the Sec insertion efficiency by SECIS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.39).
BP6
Variant 1-25805239-G-A is Benign according to our data. Variant chr1-25805239-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 530815.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BP7
Synonymous conserved (PhyloP=-0.292 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SELENON | NM_020451.3 | c.501G>A | p.Pro167Pro | synonymous_variant | 4/13 | ENST00000361547.7 | NP_065184.2 | |
SELENON | NM_206926.2 | c.399G>A | p.Pro133Pro | synonymous_variant | 3/12 | NP_996809.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SELENON | ENST00000361547.7 | c.501G>A | p.Pro167Pro | synonymous_variant | 4/13 | 1 | NM_020451.3 | ENSP00000355141.2 | ||
SELENON | ENST00000374315.1 | c.399G>A | p.Pro133Pro | synonymous_variant | 3/12 | 5 | ENSP00000363434.1 | |||
SELENON | ENST00000354177.9 | c.399G>A | p.Pro133Pro | synonymous_variant | 3/12 | 5 | ENSP00000346109.5 | |||
SELENON | ENST00000494537.2 | n.399G>A | non_coding_transcript_exon_variant | 3/13 | 3 | ENSP00000508308.1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000240 AC: 6AN: 249508Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135384
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GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461860Hom.: 0 Cov.: 34 AF XY: 0.0000261 AC XY: 19AN XY: 727228
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74324
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Eichsfeld type congenital muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 09, 2018 | This sequence change affects codon 167 of the SELENON mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SELENON protein. This variant is present in population databases (rs752707301, ExAC 0.01%). This variant has not been reported in the literature in individuals with SELENON-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 15, 2024 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at