chr1-25800232-T-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_020451.3(SELENON):c.2T>G(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 0.00000159 in 628,544 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000016 ( 0 hom. )
Consequence
SELENON
NM_020451.3 start_lost
NM_020451.3 start_lost
Scores
4
5
6
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 14 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_020451.3 (SELENON) was described as [Likely_pathogenic] in ClinVar as 4491
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-25800232-T-G is Pathogenic according to our data. Variant chr1-25800232-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 461632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-25800232-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SELENON | NM_020451.3 | c.2T>G | p.Met1? | start_lost | 1/13 | ENST00000361547.7 | |
SELENON | NM_206926.2 | c.2T>G | p.Met1? | start_lost | 1/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SELENON | ENST00000361547.7 | c.2T>G | p.Met1? | start_lost | 1/13 | 1 | NM_020451.3 | ||
SELENON | ENST00000374315.1 | c.2T>G | p.Met1? | start_lost | 1/12 | 5 | P1 | ||
SELENON | ENST00000354177.9 | c.2T>G | p.Met1? | start_lost | 1/12 | 5 | |||
SELENON | ENST00000494537.2 | c.2T>G | p.Met1? | start_lost, NMD_transcript_variant | 1/13 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD4 exome AF: 0.00000159 AC: 1AN: 628544Hom.: 0 Cov.: 8 AF XY: 0.00000342 AC XY: 1AN XY: 292422
GnomAD4 exome
AF:
AC:
1
AN:
628544
Hom.:
Cov.:
8
AF XY:
AC XY:
1
AN XY:
292422
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GnomAD4 genome ? Cov.: 30
GnomAD4 genome
?
Cov.:
30
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Eichsfeld type congenital muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 14, 2020 | This sequence change affects the initiator methionine of the SEPN1 mRNA. The next in-frame methionine is located at codon 85. For these reasons, this variant has been classified as Pathogenic. Disruption of initiator codon variants have been observed in individuals affected with clinical features of SEPN1-related disorders (PMID: 1219264, 23394784, 16779558). ClinVar contains an entry for this variant (Variation ID: 461632). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Benign
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
0.68, 0.78
.;P;P
Vest4
MutPred
Gain of methylation at M1 (P = 2e-04);Gain of methylation at M1 (P = 2e-04);Gain of methylation at M1 (P = 2e-04);
MVP
ClinPred
D
GERP RS
Varity_R
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at