1-25800211-AGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGC-A
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PS1_ModeratePP5_Very_Strong
The NM_020451.3(SELENON):c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 142,352 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_020451.3 frameshift, start_lost
Scores
Clinical Significance
Conservation
Publications
- rigid spine muscular dystrophy 1Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, G2P
- SELENON-related myopathyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- congenital myopathy 4A, autosomal dominantInheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- congenital fiber-type disproportion myopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- desmin-related myopathy with Mallory body-like inclusionsInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- rigid spine syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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SELENON | NM_020451.3 | c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC | p.Met1fs | frameshift_variant, start_lost | Exon 1 of 13 | ENST00000361547.7 | NP_065184.2 | |
SELENON | NM_020451.3 | c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC | 5_prime_UTR_variant | Exon 1 of 13 | ENST00000361547.7 | NP_065184.2 | ||
SELENON | NM_206926.2 | c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC | p.Met1fs | frameshift_variant, start_lost | Exon 1 of 12 | NP_996809.1 | ||
SELENON | NM_206926.2 | c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC | 5_prime_UTR_variant | Exon 1 of 12 | NP_996809.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SELENON | ENST00000361547.7 | c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC | p.Met1fs | frameshift_variant, start_lost | Exon 1 of 13 | 1 | NM_020451.3 | ENSP00000355141.2 | ||
SELENON | ENST00000361547.7 | c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC | 5_prime_UTR_variant | Exon 1 of 13 | 1 | NM_020451.3 | ENSP00000355141.2 |
Frequencies
GnomAD3 genomes AF: 0.0000140 AC: 2AN: 142352Hom.: 0 Cov.: 30 show subpopulations
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000174 AC: 6AN: 344628Hom.: 0 AF XY: 0.00000621 AC XY: 1AN XY: 160964 show subpopulations
GnomAD4 genome AF: 0.0000140 AC: 2AN: 142352Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 69086 show subpopulations
ClinVar
Submissions by phenotype
Eichsfeld type congenital muscular dystrophy Pathogenic:4
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This sequence change affects the initiator methionine of the SELENON mRNA. The next in-frame methionine is located at codon 85. This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of the initiator codon has been observed in individual(s) with autosomal recessive SELENON-related myopathy (PMID: 16365872, 28688748). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.-19_+73del92 and c.1-11_81del92. ClinVar contains an entry for this variant (Variation ID: 373075). For these reasons, this variant has been classified as Pathogenic. -
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Congenital myopathy with fiber type disproportion Pathogenic:1
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not provided Pathogenic:1
The c.-11_81del92 variant in the SEPN1 gene has been reported previously, using alternate nomenclature c.-19_+73del92, in the homozygous state in one family with Mallory-body myopathy (Ferreiro et al., 2004), and in a patient with multiminicore disease who was heterozygous for the c.-11_81del92 variant and heterozygous for another SEPN1 variant (Clarke et al., 2006). The c.-11_81del92 variant causes the deletion of 92 nucleotides starting upstream of and including the ATG translational start site. It is not known if the loss of the translation start codon means that all protein translation is completed prevented, or if an abnormal protein is produced using an alternate Methionine. No data from control populations were available to assess the frequency of this variant. We interpret c.-11_81del92 as a pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at