rs368104077

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_020451.3(SELENON):c.713dup(p.Asn238LysfsTer?) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SELENON
NM_020451.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 7.33

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]

SELENON links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-25808753-C-CA is Pathogenic according to our data. Variant chr1-25808753-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 4494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3 linkuse as main transcript	c.713dup	p.Asn238LysfsTer?	frameshift_variant	5/13	ENST00000361547.7
SELENON	NM_206926.2 linkuse as main transcript	c.611dup	p.Asn204LysfsTer63	frameshift_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7 linkuse as main transcript	c.713dup	p.Asn238LysfsTer?	frameshift_variant	5/13	1	NM_020451.3		Q9NZV5-1
SELENON	ENST00000354177.9 linkuse as main transcript	c.611dup	p.Asn204LysfsTer40	frameshift_variant	4/12	5
SELENON	ENST00000374315.1 linkuse as main transcript	c.611dup	p.Asn204LysfsTer63	frameshift_variant	4/12	5		P1	Q9NZV5-2
SELENON	ENST00000494537.2 linkuse as main transcript	c.611dup	p.Asn204LysfsTer63	frameshift_variant, NMD_transcript_variant	4/13	3

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000157

AC:

AN:

249200

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

135294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000114

AC:

167

AN:

1461624

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000564

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000118

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000206

Hom.:

Bravo

AF:

0.000117

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 26, 2024	Criteria applied: PVS1,PM3_STR,PM2_SUP; Identified as compund heterozygous with NM_020451.2:c.1282-13G>A -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.713dup;p.(Asn238Lysfs*63) is a null frameshift variant (NMD) in the SELENON gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 4494; OMIM: 606210.0006; PMID: 12192640; 27447704; 15792869; 17951086) - PS4. The variant is present at low allele frequencies population databases (rs368104077– gnomAD 0.01182%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2023	Variant summary: SELENON c.713dupA (p.Asn238LysfsX63) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 249200 control chromosomes (gnomAD). This frequency is not higher than estimated maximum expected for a pathogenic variant in SELENON causing Congenital Muscular Dystrophy (0.0011). The variant, c.713dupA, has been reported in the literature in several individuals affected with Muscular Dystrophy (Ferreiro_2002, Herasse_2007, Schara_2008, Villar-Quiles_2020), in at least one homozygous case, the absence of the protein was noted to be verified by western blot on patient derived fibroblasts (Herasse_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 14, 2023	This sequence change creates a premature translational stop signal (p.Asn238Lysfs*63) in the SELENON gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SELENON are known to be pathogenic (PMID: 21131290, 21670436). This variant is present in population databases (rs750857935, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with SELENON-related conditions (PMID: 12192640, 15792869, 17951086, 27447704). ClinVar contains an entry for this variant (Variation ID: 4494). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2023	The homozygous p.Asn238fs variant in SELENON was identified by our study in one individual with SELENON-RM. The variant has been reported in at least 10 individuals with SELENON-RM (PMID: 12192640, 15792869, 19557870, 27447704, 30612914, 3093229, 33652732, 32661288, 16498447, 17951086), segregated with disease in 1 affected relative from 1 family (PMID: 33652732), and has been identified in 0.1% (14/10348) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs750857935). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 4494) and has been interpreted as pathogenic by multiple submitters. Of the more than 10 affected individuals, at least 4 of those were homozygotes and 1 was a compound heterozygote that carried a reported pathogenic variants in trans, which increases the likelihood that the p.Asn238fs variant is pathogenic (VariationID: 95958; PMID: 12192640, 16498447, 19557870, 32661288, 33652732, 15792869). In vitro functional studies provide some evidence that the p.Asn238fs variant may impact protein function (PMID: 19067361). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein‚Äôs amino acid sequence beginning at position 238 and leads to a premature termination codon 63 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SELENON gene is an established disease mechanism in autosomal recessive SELENON-RM. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive SELENON-RM. ACMG/AMP Criteria applied: PVS1, PS3_moderate, PM3_strong (Richards 2015). -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 12192640, 19067361, 15792869, 17951086, 16498447, 27447704, 30612914, 30932294, 31321302, 31127727, 33652732) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	SELENON: PM3:Strong, PVS1:Strong, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 26, 2017	- -

Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Jan 22, 2021	The variant c.713dup (p.Asn238fs*62) in the SELENON gene is reported as a pathogenic for SELENON-related disorders in ClinVar (Variation ID: 4494) and as affecting function in the Global Variome shared LOVD v.3.0 database. The variant creates a shift in the reading frame, which is predicted to result in a premature stop codon 62 amino acids downstream, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant was reported as pathogenic by Ferreiro et al., 2002 (PMID: 12192640) in two patients with multiminicore disease. In one patient the variant was in a state of homozygosity, in the other in compound heterozygosity with a missense mutation. In other studies (StehlÃkovÃ¡ et al., 2017, PMID: 27447704; Tajsharghi et al., 2005, PMID: 15792869) the variant was identified in a compound heterozygous state with another mutation in a court of patients with congenital myopathies. In Schara et al., 2008 (PMID: 17951086) the variant was identified in heterozygosity in two patients with myopathy with delayed motor acquisition, hypotonia and lack of head control. It should be noted that the authors could not identify a second mutation in the other allele in these patients, and argue that a large deletion of one or more exons in the gene could constitute the mutation not identified by the sequencing technique used. The variant is reported with an estimated allelic frequency of 0.0001565 in gnomAD exomes and 0.0001912 in gnomAD genomes, with no homozygous individuals reported. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 11, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over