rs147587542

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_020451.3(SELENON):c.981C>T(p.Arg327=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 1,613,980 control chromosomes in the GnomAD database, including 1,486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 73 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1413 hom. )

Consequence

SELENON
NM_020451.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.77

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 1-25809791-C-T is Benign according to our data. Variant chr1-25809791-C-T is described in ClinVar as [Benign]. Clinvar id is 95967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25809791-C-T is described in Lovd as [Benign]. Variant chr1-25809791-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.77 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0269 (4095/152320) while in subpopulation NFE AF= 0.0434 (2949/68018). AF 95% confidence interval is 0.0421. There are 73 homozygotes in gnomad4. There are 1877 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 73 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3 linkuse as main transcript	c.981C>T	p.Arg327=	synonymous_variant	7/13	ENST00000361547.7
SELENON	NM_206926.2 linkuse as main transcript	c.879C>T	p.Arg293=	synonymous_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7 linkuse as main transcript	c.981C>T	p.Arg327=	synonymous_variant	7/13	1	NM_020451.3		Q9NZV5-1
SELENON	ENST00000374315.1 linkuse as main transcript	c.879C>T	p.Arg293=	synonymous_variant	6/12	5		P1	Q9NZV5-2
SELENON	ENST00000354177.9 linkuse as main transcript	c.810C>T	p.Arg270=	synonymous_variant	6/12	5
SELENON	ENST00000494537.2 linkuse as main transcript	c.879C>T	p.Arg293=	synonymous_variant, NMD_transcript_variant	6/13	3

Frequencies

GnomAD3 genomes

AF:

0.0269

AC:

4096

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00844

Gnomad AMI

AF:

0.0516

Gnomad AMR

AF:

0.0245

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00684

Gnomad FIN

AF:

0.0187

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0434

Gnomad OTH

AF:

0.0306

GnomAD3 exomes

AF:

0.0256

AC:

6380

AN:

249420

Hom.:

114

AF XY:

0.0250

AC XY:

3380

AN XY:

135350

show subpopulations

Gnomad AFR exome

AF:

0.00735

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0217

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00542

Gnomad FIN exome

AF:

0.0180

Gnomad NFE exome

AF:

0.0411

Gnomad OTH exome

AF:

0.0292

GnomAD4 exome

AF:

0.0393

AC:

57506

AN:

1461660

Hom.:

1413

Cov.:

AF XY:

0.0384

AC XY:

27902

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00600

Gnomad4 AMR exome

AF:

0.0195

Gnomad4 ASJ exome

AF:

0.0254

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00649

Gnomad4 FIN exome

AF:

0.0181

Gnomad4 NFE exome

AF:

0.0470

Gnomad4 OTH exome

AF:

0.0328

GnomAD4 genome

AF:

0.0269

AC:

4095

AN:

152320

Hom.:

Cov.:

AF XY:

0.0252

AC XY:

1877

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00842

Gnomad4 AMR

AF:

0.0245

Gnomad4 ASJ

AF:

0.0210

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00663

Gnomad4 FIN

AF:

0.0187

Gnomad4 NFE

AF:

0.0434

Gnomad4 OTH

AF:

0.0303

Alfa

AF:

0.0372

Hom.:

Bravo

AF:

0.0268

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0376

EpiControl

AF:

0.0376

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2017	p.Arg327Arg in exon 7 of SEPN1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 3.8% (2526/66692) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs147587542). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 30, 2019	- -

SEPN1-Related Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Eichsfeld type congenital muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

Cadd

Benign

0.18

Dann

Benign

0.90

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.

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