rs2294228

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 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

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:

ENSG00000255054 (HGNC:):

ENSG00000255054 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 95959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25814082-C-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
SELENON	NM_020451.3 link	c.1506C>A	p.Asn502Lys	missense_variant	12/13	ENST00000361547.7	NP_065184.2	Q9NZV5-1
SELENON	NM_206926.2 link	c.1404C>A	p.Asn468Lys	missense_variant	11/12		NP_996809.1	Q9NZV5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7 link	c.1506C>A	p.Asn502Lys	missense_variant	12/13	1	NM_020451.3	ENSP00000355141.2		Q9NZV5-1
ENSG00000255054	ENST00000527604.1 link	n.27C>A		non_coding_transcript_exon_variant	2/4	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

GnomAD3 exomes

AF:

0.786

AC:

196103

AN:

249356

Hom.:

79733

AF XY:

0.794

AC XY:

107435

AN XY:

135286

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 SAS exome

AF:

0.877

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

Gnomad4 AFR exome

AF:

0.284

Gnomad4 AMR exome

AF:

0.870

Gnomad4 ASJ exome

AF:

0.769

Gnomad4 EAS exome

AF:

0.961

Gnomad4 SAS exome

AF:

0.878

Gnomad4 FIN exome

AF:

0.744

Gnomad4 NFE exome

AF:

0.786

Gnomad4 OTH exome

AF:

0.772

GnomAD4 genome

AF:

0.658

AC:

100115

AN:

152098

Hom.:

36901

Cov.:

AF XY:

0.665

AC XY:

49453

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.301

Gnomad4 AMR

AF:

0.793

Gnomad4 ASJ

AF:

0.765

Gnomad4 EAS

AF:

0.966

Gnomad4 SAS

AF:

0.886

Gnomad4 FIN

AF:

0.755

Gnomad4 NFE

AF:

0.780

Gnomad4 OTH

AF:

0.703

Alfa

AF:

0.769

Hom.:

97534

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

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Eichsfeld type congenital muscular dystrophy

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

SEPN1-related disorder

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

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;.

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

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

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