rs753400008

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_020451.3(SELENON):​c.979C>T​(p.Arg327Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,686 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R327H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SELENON
NM_020451.3 missense

Scores

7
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.94
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SELENONNM_020451.3 linkc.979C>T p.Arg327Cys missense_variant Exon 7 of 13 ENST00000361547.7 NP_065184.2 Q9NZV5-1
SELENONNM_206926.2 linkc.877C>T p.Arg293Cys missense_variant Exon 6 of 12 NP_996809.1 Q9NZV5-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SELENONENST00000361547.7 linkc.979C>T p.Arg327Cys missense_variant Exon 7 of 13 1 NM_020451.3 ENSP00000355141.2 Q9NZV5-1
SELENONENST00000374315.1 linkc.877C>T p.Arg293Cys missense_variant Exon 6 of 12 5 ENSP00000363434.1 Q9NZV5-2
SELENONENST00000354177.9 linkc.808C>T p.Arg270Cys missense_variant Exon 6 of 12 5 ENSP00000346109.5 H9KV50
SELENONENST00000494537.2 linkn.877C>T non_coding_transcript_exon_variant Exon 6 of 13 3 ENSP00000508308.1 A0A804HLD6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000802
AC:
2
AN:
249426
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135360
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461686
Hom.:
0
Cov.:
32
AF XY:
0.00000825
AC XY:
6
AN XY:
727154
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113
ExAC
AF:
0.00000825
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2025This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 327 of the SELENON protein (p.Arg327Cys). This variant is present in population databases (rs753400008, gnomAD 0.006%). 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: 461636). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.60
.;D;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.84
D;D;D
MetaSVM
Uncertain
0.68
D
MutationAssessor
Uncertain
2.2
.;M;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-4.6
D;D;D
REVEL
Pathogenic
0.80
Sift
Benign
0.061
T;T;T
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.94
MutPred
0.53
.;Loss of sheet (P = 0.1158);.;
MVP
0.98
MPC
0.96
ClinPred
0.95
D
GERP RS
4.8
Varity_R
0.28

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs753400008; hg19: chr1-26136280; API