rs760063405
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_020451.3(SELENON):c.1375C>T(p.Gln459Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_020451.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SELENON | NM_020451.3 | c.1375C>T | p.Gln459Ter | stop_gained | 10/13 | ENST00000361547.7 | |
SELENON | NM_206926.2 | c.1273C>T | p.Gln425Ter | stop_gained | 9/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SELENON | ENST00000361547.7 | c.1375C>T | p.Gln459Ter | stop_gained | 10/13 | 1 | NM_020451.3 | ||
SELENON | ENST00000374315.1 | c.1273C>T | p.Gln425Ter | stop_gained | 9/12 | 5 | P1 | ||
SELENON | ENST00000354177.9 | c.1204C>T | p.Gln402Ter | stop_gained | 9/12 | 5 | |||
SELENON | ENST00000494537.2 | c.1273C>T | p.Gln425Ter | stop_gained, NMD_transcript_variant | 9/13 | 3 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000812 AC: 2AN: 246280Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 133954
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460572Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726476
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Eichsfeld type congenital muscular dystrophy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | The p.Gln459Ter variant in SELENON has not been previously reported in the literature in individuals with SELENON-RM but has been identified in 0.002% (2/111632) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs760063405). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 575921) and has been interpreted as likely pathogenic by Invitae. This nonsense variant leads to a premature termination codon at position 459 which is 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive SELENON-RM. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 08, 2019 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SELENON are known to be pathogenic (PMID: 21131290, 21670436). This variant has not been reported in the literature in individuals with SELENON-related disease. This variant is present in population databases (rs760063405, ExAC 0.003%). This sequence change creates a premature translational stop signal (p.Gln459*) in the SELENON gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at