rs775897489
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_020451.3(SELENON):āc.935A>Gā(p.Gln312Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,936 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.000043 ( 1 hom. )
Consequence
SELENON
NM_020451.3 missense
NM_020451.3 missense
Scores
6
8
2
Clinical Significance
Conservation
PhyloP100: 9.08
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SELENON | NM_020451.3 | c.935A>G | p.Gln312Arg | missense_variant | 7/13 | ENST00000361547.7 | |
SELENON | NM_206926.2 | c.833A>G | p.Gln278Arg | missense_variant | 6/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SELENON | ENST00000361547.7 | c.935A>G | p.Gln312Arg | missense_variant | 7/13 | 1 | NM_020451.3 | ||
SELENON | ENST00000374315.1 | c.833A>G | p.Gln278Arg | missense_variant | 6/12 | 5 | P1 | ||
SELENON | ENST00000354177.9 | c.764A>G | p.Gln255Arg | missense_variant | 6/12 | 5 | |||
SELENON | ENST00000494537.2 | c.833A>G | p.Gln278Arg | missense_variant, NMD_transcript_variant | 6/13 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152106Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249528Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135402
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GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461830Hom.: 1 Cov.: 32 AF XY: 0.0000509 AC XY: 37AN XY: 727220
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152106Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74286
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 13, 2021 | The c.935A>G (p.Q312R) alteration is located in exon 7 (coding exon 7) of the SEPN1 gene. This alteration results from a A to G substitution at nucleotide position 935, causing the glutamine (Q) at amino acid position 312 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Eichsfeld type congenital muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 312 of the SELENON protein (p.Gln312Arg). This variant is present in population databases (rs775897489, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SELENON-related conditions. ClinVar contains an entry for this variant (Variation ID: 579099). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SELENON protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
D;T;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;N;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
0.85, 0.91
.;P;P
Vest4
MutPred
0.41
.;Gain of phosphorylation at T314 (P = 0.1558);.;
MVP
MPC
0.90
ClinPred
D
GERP RS
Varity_R
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at