rs1174570887
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_020451.3(SELENON):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000695 in 143,788 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 (★★).
Frequency
Genomes: 𝑓 0.0000070 ( 0 hom., cov: 30)
Consequence
SELENON
NM_020451.3 start_lost
NM_020451.3 start_lost
Scores
5
4
7
Clinical Significance
Conservation
PhyloP100: -1.62
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 20 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_020451.3 (SELENON) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-25800232-T-A is Pathogenic according to our data. Variant chr1-25800232-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1701096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SELENON | NM_020451.3 | c.2T>A | p.Met1? | start_lost | 1/13 | ENST00000361547.7 | NP_065184.2 | |
SELENON | NM_206926.2 | c.2T>A | p.Met1? | start_lost | 1/12 | NP_996809.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SELENON | ENST00000361547.7 | c.2T>A | p.Met1? | start_lost | 1/13 | 1 | NM_020451.3 | ENSP00000355141 | ||
SELENON | ENST00000374315.1 | c.2T>A | p.Met1? | start_lost | 1/12 | 5 | ENSP00000363434 | P1 | ||
SELENON | ENST00000354177.9 | c.2T>A | p.Met1? | start_lost | 1/12 | 5 | ENSP00000346109 | |||
SELENON | ENST00000494537.2 | c.2T>A | p.Met1? | start_lost, NMD_transcript_variant | 1/13 | 3 | ENSP00000508308 |
Frequencies
GnomAD3 genomes AF: 0.00000695 AC: 1AN: 143788Hom.: 0 Cov.: 30
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GnomAD4 genome AF: 0.00000695 AC: 1AN: 143788Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 69862
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Eichsfeld type congenital muscular dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Breakthrough Genomics, Breakthrough Genomics | Apr 30, 2021 | This variant has not been previously reported in population or public databases or in the literature. However, two other substitution variants affecting this residue such as; c.2T>C; p.M1T and c.2T>G ;M1R has been previously reported as ‘pathogenic’ in the context of Eichsfeld type congenital muscular dystrophy. In addition, variants disrupting the initiator codon such as; p.Met1Val and c.2dup (represented as 1_2insT in the article) have been previously observed in multiple unrelated individuals of various ethnic origins affected with SELENON-related congenital myopathies and muscular dystrophy [PMID: 1219264, 23394784, 16779558] - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
0.46, 0.60
.;P;P
Vest4
MutPred
Loss of stability (P = 0.0274);Loss of stability (P = 0.0274);Loss of stability (P = 0.0274);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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