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

Scores

5
4
7

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: -1.62
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 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
SELENONNM_020451.3 linkuse as main transcriptc.2T>A p.Met1? start_lost 1/13 ENST00000361547.7 NP_065184.2
SELENONNM_206926.2 linkuse as main transcriptc.2T>A p.Met1? start_lost 1/12 NP_996809.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SELENONENST00000361547.7 linkuse as main transcriptc.2T>A p.Met1? start_lost 1/131 NM_020451.3 ENSP00000355141 Q9NZV5-1
SELENONENST00000374315.1 linkuse as main transcriptc.2T>A p.Met1? start_lost 1/125 ENSP00000363434 P1Q9NZV5-2
SELENONENST00000354177.9 linkuse as main transcriptc.2T>A p.Met1? start_lost 1/125 ENSP00000346109
SELENONENST00000494537.2 linkuse as main transcriptc.2T>A p.Met1? start_lost, NMD_transcript_variant 1/133 ENSP00000508308

Frequencies

GnomAD3 genomes
AF:
0.00000695
AC:
1
AN:
143788
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000154
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
8
GnomAD4 genome
AF:
0.00000695
AC:
1
AN:
143788
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
69862
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000154
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

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 submitterclinical testingBreakthrough Genomics, Breakthrough GenomicsApr 30, 2021This 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Benign
15
DANN
Benign
0.95
DEOGEN2
Benign
0.092
.;T;.
Eigen
Benign
-0.40
Eigen_PC
Benign
-0.48
FATHMM_MKL
Benign
0.030
N
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.95
D;D;D
MetaSVM
Uncertain
-0.041
T
MutationTaster
Benign
1.0
D;D;D
PROVEAN
Benign
-0.43
N;N;N
REVEL
Uncertain
0.53
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.46, 0.60
.;P;P
Vest4
0.27
MutPred
0.99
Loss of stability (P = 0.0274);Loss of stability (P = 0.0274);Loss of stability (P = 0.0274);
MVP
0.91
ClinPred
0.97
D
GERP RS
2.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92

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: rs1174570887; hg19: chr1-26126723; API