chr1-25800233-G-GGGCCGGGCCC
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_020451.3(SELENON):c.13_22dupCGGCCGGGCC(p.Gln8fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 799,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000082 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000077 ( 0 hom. )
Consequence
SELENON
NM_020451.3 frameshift
NM_020451.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.219
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 142 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-25800233-G-GGGCCGGGCCC is Pathogenic according to our data. Variant chr1-25800233-G-GGGCCGGGCCC is described in ClinVar as [Pathogenic]. Clinvar id is 193432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SELENON | ENST00000361547.7 | c.13_22dupCGGCCGGGCC | p.Gln8fs | frameshift_variant | 1/13 | 1 | NM_020451.3 | ENSP00000355141.2 | ||
| SELENON | ENST00000374315.1 | c.13_22dupCGGCCGGGCC | p.Gln8fs | frameshift_variant | 1/12 | 5 | ENSP00000363434.1 | |||
| SELENON | ENST00000354177.9 | c.13_22dupCGGCCGGGCC | p.Gln8fs | frameshift_variant | 1/12 | 5 | ENSP00000346109.5 | |||
| SELENON | ENST00000494537.2 | n.13_22dupCGGCCGGGCC | non_coding_transcript_exon_variant | 1/13 | 3 | ENSP00000508308.1 |
Frequencies
GnomAD3 genomes 0.0000824 AC: 12AN: 145566Hom.: 0 Cov.: 30
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GnomAD4 exome AF: 0.00000765 AC: 5AN: 653544Hom.: 0 Cov.: 8 AF XY: 0.00000658 AC XY: 2AN XY: 304040
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GnomAD4 genome 0.0000824 AC: 12AN: 145628Hom.: 0 Cov.: 30 AF XY: 0.0000706 AC XY: 5AN XY: 70856
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Eichsfeld type congenital muscular dystrophy Pathogenic:4
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | The p.Gln8fs variant in SELENON has been reported in 9 individuals with SELENON-RM (PMID: 19557870, 20937510, 23394784, 11528383, 29669168, 33726816, 30921636), segregated with disease in 2 affected relatives from 1 family (PMID: 11528383), and has been identified in 0.03% (2/7988) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs970951421). Data from large population studies is insufficient to assess the frequency of this variant. Of the 9 affected individuals, 5 of those were homozygotes and 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Gln8fs variant is pathogenic (PMID: 11528383, 19557870, 23394784, 30921636). This variant has also been reported in ClinVar (Variation ID#: 193432) and has been interpreted as pathogenic by Invitae and Eurofins NTD (LLC). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 8 and leads to a premature termination codon 78 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SELENON gene is an established disease mechanism in autosomal recessive SELENON-RM. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive SELENON-RM. ACMG/AMP Criteria applied: PVS1, PP1, PM3_strong (Richards 2015). - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 16, 2023 | This sequence change creates a premature translational stop signal (p.Gln8Profs*78) in the SELENON gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SELENON are known to be pathogenic (PMID: 21131290, 21670436). This variant is present in population databases (rs797044621, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with congenital muscular dystrophy with spinal rigidity and/or congenital myopathy (PMID: 11528383, 19557870, 20937510, 23394784). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 22dup10bp. ClinVar contains an entry for this variant (Variation ID: 193432). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 17, 2023 | Variant summary: SELENON c.13_22dup10 (p.Gln8ProfsX78) 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 by our laboratory. The variant allele was found at a frequency of 0.00012 in 24242 control chromosomes. c.13_22dup10 has been reported as homozygous and compound heterozygous genotype in the literature in multiple individuals affected with Eichsfeld Type Congenital Muscular Dystrophy (example: Moghadaszadeh_2001) and related SEPN1 myopathies (example: Park_2018, Schara_2008, Scoto_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 15, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 23, 2024 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29669168, 33726816, 35368679, 11528383, 19557870, 20937510, 24465259, 32796131, 12192640, 16498447, 37807786, 37273706, 17951086, 21670436, 23394784, 30921636, 35599849) - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at