rs2294228

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_020451.3(SELENON):c.1506C>A(p.Asn502Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 1,613,192 control chromosomes in the GnomAD database, including 493,293 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N502Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.66 ( 36901 hom., cov: 32)

Exomes 𝑓: 0.79 ( 456392 hom. )

Consequence

SELENON
NM_020451.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.140

Publications

46 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 -16 ACMG points.

BP6

Variant 1-25814082-C-A is Benign according to our data. Variant chr1-25814082-C-A is described in ClinVar as Benign. ClinVar VariationId is 95959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3 link	c.1506C>A	p.Asn502Lys	missense_variant	Exon 12 of 13	ENST00000361547.7	NP_065184.2	Q9NZV5-1
SELENON	NM_206926.2 link	c.1404C>A	p.Asn468Lys	missense_variant	Exon 11 of 12		NP_996809.1	Q9NZV5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7 link	c.1506C>A	p.Asn502Lys	missense_variant	Exon 12 of 13	1	NM_020451.3	ENSP00000355141.2		Q9NZV5-1
ENSG00000255054	ENST00000527604.1 link	n.27C>A		non_coding_transcript_exon_variant	Exon 2 of 4	5		ENSP00000457066.1		H3BT81

Frequencies

GnomAD3 genomes

AF:

0.659

AC:

100083

AN:

151980

Hom.:

36889

Cov.:

show subpopulations

Gnomad AFR

AF:

0.301

Gnomad AMI

AF:

0.939

Gnomad AMR

AF:

0.792

Gnomad ASJ

AF:

0.765

Gnomad EAS

AF:

0.966

Gnomad SAS

AF:

0.887

Gnomad FIN

AF:

0.755

Gnomad MID

AF:

0.854

Gnomad NFE

AF:

0.780

Gnomad OTH

AF:

0.701

GnomAD2 exomes

AF:

0.786

AC:

196103

AN:

249356

AF XY:

0.794

show subpopulations

Gnomad AFR exome

AF:

0.291

Gnomad AMR exome

AF:

0.879

Gnomad ASJ exome

AF:

0.771

Gnomad EAS exome

AF:

0.965

Gnomad FIN exome

AF:

0.743

Gnomad NFE exome

AF:

0.782

Gnomad OTH exome

AF:

0.795

GnomAD4 exome

AF:

0.785

AC:

1147072

AN:

1461094

Hom.:

456392

Cov.:

AF XY:

0.789

AC XY:

573642

AN XY:

726922

show subpopulations

African (AFR)

AF:

0.284

AC:

9497

AN:

33462

American (AMR)

AF:

0.870

AC:

38912

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

20089

AN:

26130

East Asian (EAS)

AF:

0.961

AC:

38131

AN:

39696

South Asian (SAS)

AF:

0.878

AC:

75691

AN:

86250

European-Finnish (FIN)

AF:

0.744

AC:

39742

AN:

53400

Middle Eastern (MID)

AF:

0.803

AC:

4634

AN:

5768

European-Non Finnish (NFE)

AF:

0.786

AC:

873751

AN:

1111294

Other (OTH)

AF:

0.772

AC:

46625

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

13436

26873

40309

53746

67182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20558

41116

61674

82232

102790

<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:

0.658

AC:

100115

AN:

152098

Hom.:

36901

Cov.:

AF XY:

0.665

AC XY:

49453

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.301

AC:

12481

AN:

41454

American (AMR)

AF:

0.793

AC:

12110

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.765

AC:

2657

AN:

3472

East Asian (EAS)

AF:

0.966

AC:

4999

AN:

5174

South Asian (SAS)

AF:

0.886

AC:

4282

AN:

4834

European-Finnish (FIN)

AF:

0.755

AC:

8003

AN:

10598

Middle Eastern (MID)

AF:

0.854

AC:

251

AN:

294

European-Non Finnish (NFE)

AF:

0.780

AC:

52989

AN:

67966

Other (OTH)

AF:

0.703

AC:

1487

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1388

2777

4165

5554

6942

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

768

1536

2304

3072

3840

<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:

0.751

Hom.:

182828

Bravo

AF:

0.646

TwinsUK

AF:

0.788

AC:

2923

ALSPAC

AF:

0.789

AC:

3041

ESP6500AA

AF:

0.324

AC:

1388

ESP6500EA

AF:

0.787

AC:

6682

ExAC

AF:

0.773

AC:

93611

Asia WGS

AF:

0.885

AC:

3076

AN:

3478

EpiCase

AF:

0.795

EpiControl

AF:

0.799

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This is a RefSeq error. The reference base (c.1506C) is the minor allele. This a llele (C) has been identified in 21% (1806/8488) of European American chromosome s and 67% (2894/4282) of African American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs2294228) and thus meets criteria to be classified as benign. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 05, 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. -

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 07, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Eichsfeld type congenital muscular dystrophy

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 13, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

.;T;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.59

T;T;T

MetaRNN

Benign

8.1e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

.;L;.

PhyloP100

0.14

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Benign

0.085

Sift

Benign

0.11

T;T;D

Sift4G

Uncertain

0.020

D;D;D

Polyphen

0.0

.;B;B

Vest4

0.028

MutPred

0.25

.;Gain of ubiquitination at N502 (P = 0.0025);.;

MPC

0.27

ClinPred

0.012

GERP RS

2.6

Varity_R

0.083

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.33

Position offset: 22

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