1-25809791-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_020451.3(SELENON):c.981C>T(p.Arg327Arg) 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:11

Conservation

PhyloP100: -2.77

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

rigid spine muscular dystrophy 1
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, G2P
SELENON-related myopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
congenital myopathy 4A, autosomal dominant
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
congenital fiber-type disproportion myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
desmin-related myopathy with Mallory body-like inclusions
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
rigid spine syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SELENON links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 95967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 73 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3 link	c.981C>T	p.Arg327Arg	synonymous_variant	Exon 7 of 13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2 link	c.879C>T	p.Arg293Arg	synonymous_variant	Exon 6 of 12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SELENON	ENST00000361547.7 link	c.981C>T	p.Arg327Arg	synonymous_variant	Exon 7 of 13	1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1 link	c.879C>T	p.Arg293Arg	synonymous_variant	Exon 6 of 12	5		ENSP00000363434.1
SELENON	ENST00000354177.9 link	c.810C>T	p.Arg270Arg	synonymous_variant	Exon 6 of 12	5		ENSP00000346109.5
SELENON	ENST00000494537.2 link	n.879C>T		non_coding_transcript_exon_variant	Exon 6 of 13	3		ENSP00000508308.1

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

GnomAD2 exomes

AF:

0.0256

AC:

6380

AN:

249420

AF XY:

0.0250

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 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

African (AFR)

AF:

0.00600

AC:

201

AN:

33480

American (AMR)

AF:

0.0195

AC:

872

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0254

AC:

665

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00649

AC:

560

AN:

86258

European-Finnish (FIN)

AF:

0.0181

AC:

964

AN:

53220

Middle Eastern (MID)

AF:

0.00607

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0470

AC:

52225

AN:

1111982

Other (OTH)

AF:

0.0328

AC:

1983

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

3380

6760

10140

13520

16900

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1926

3852

5778

7704

9630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0269

AC:

4095

AN:

152320

Hom.:

Cov.:

AF XY:

0.0252

AC XY:

1877

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00842

AC:

350

AN:

41576

American (AMR)

AF:

0.0245

AC:

375

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00663

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0187

AC:

198

AN:

10614

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0434

AC:

2949

AN:

68018

Other (OTH)

AF:

0.0303

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

208

416

624

832

1040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0364

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 10, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Jan 13, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

SEPN1-related disorder

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.18

(source)

DANN

Benign

0.90

PhyloP100

-2.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over