NM_020451.3:c.1092+6C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020451.3(SELENON):c.1092+6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00982 in 1,613,672 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 13 hom., cov: 33)

Exomes 𝑓: 0.010 ( 107 hom. )

Consequence

SELENON
NM_020451.3 splice_region, intron

Scores

Splicing: ADA: 0.00003976

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.0720

Publications

2 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:

ENSG00000255054 (HGNC:):

ENSG00000255054 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 1-25811541-C-G is Benign according to our data. Variant chr1-25811541-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00732 (1115/152296) while in subpopulation NFE AF = 0.0123 (836/68024). AF 95% confidence interval is 0.0116. There are 13 homozygotes in GnomAd4. There are 520 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3 link	c.1092+6C>G		splice_region_variant, intron_variant	Intron 8 of 12	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2 link	c.990+6C>G		splice_region_variant, intron_variant	Intron 7 of 11		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7 link	c.1092+6C>G		splice_region_variant, intron_variant	Intron 8 of 12	1	NM_020451.3	ENSP00000355141.2

Frequencies

GnomAD3 genomes

AF:

0.00733

AC:

1115

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00641

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00775

AC:

1934

AN:

249452

AF XY:

0.00811

show subpopulations

Gnomad AFR exome

AF:

0.00207

Gnomad AMR exome

AF:

0.00437

Gnomad ASJ exome

AF:

0.00765

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00359

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.0101

AC:

14739

AN:

1461376

Hom.:

107

Cov.:

AF XY:

0.0102

AC XY:

7393

AN XY:

727016

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

33476

American (AMR)

AF:

0.00452

AC:

202

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00666

AC:

174

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00608

AC:

524

AN:

86246

European-Finnish (FIN)

AF:

0.00414

AC:

221

AN:

53320

Middle Eastern (MID)

AF:

0.0281

AC:

162

AN:

5766

European-Non Finnish (NFE)

AF:

0.0116

AC:

12841

AN:

1111630

Other (OTH)

AF:

0.00908

AC:

548

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

790

1580

2371

3161

3951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

456

912

1368

1824

2280

<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:

0.00732

AC:

1115

AN:

152296

Hom.:

Cov.:

AF XY:

0.00698

AC XY:

520

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

41558

American (AMR)

AF:

0.00542

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00642

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00311

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0123

AC:

836

AN:

68024

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

126

188

251

314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00806

Hom.:

Bravo

AF:

0.00724

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0141

EpiControl

AF:

0.0134

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 18, 2016

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 05, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 11, 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. -

not provided

Benign:3

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SELENON: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 02, 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

-0.82

CADD

Benign

2.4

(source)

DANN

Benign

0.70

PhyloP100

-0.072

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000040

dbscSNV1_RF

Benign

0.026

SpliceAI score (max)

0.050

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