rs7349185

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020451.3(SELENON):c.425G>A(p.Cys142Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 1,613,436 control chromosomes in the GnomAD database, including 514,758 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 48238 hom., cov: 30)

Exomes 𝑓: 0.80 ( 466520 hom. )

Consequence

SELENON
NM_020451.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.869

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.500975E-7).

BP6

Variant 1-25805163-G-A is Benign according to our data. Variant chr1-25805163-G-A is described in ClinVar as [Benign]. Clinvar id is 95963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25805163-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3 linkuse as main transcript	c.425G>A	p.Cys142Tyr	missense_variant	4/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2 linkuse as main transcript	c.323G>A	p.Cys108Tyr	missense_variant	3/12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7 linkuse as main transcript	c.425G>A	p.Cys142Tyr	missense_variant	4/13	1	NM_020451.3	ENSP00000355141		Q9NZV5-1
SELENON	ENST00000374315.1 linkuse as main transcript	c.323G>A	p.Cys108Tyr	missense_variant	3/12	5		ENSP00000363434	P1	Q9NZV5-2
SELENON	ENST00000354177.9 linkuse as main transcript	c.323G>A	p.Cys108Tyr	missense_variant	3/12	5		ENSP00000346109
SELENON	ENST00000494537.2 linkuse as main transcript	c.323G>A	p.Cys108Tyr	missense_variant, NMD_transcript_variant	3/13	3		ENSP00000508308

Frequencies

GnomAD3 genomes

AF:

0.795

AC:

120726

AN:

151832

Hom.:

48208

Cov.:

show subpopulations

Gnomad AFR

AF:

0.781

Gnomad AMI

AF:

0.962

Gnomad AMR

AF:

0.853

Gnomad ASJ

AF:

0.782

Gnomad EAS

AF:

0.935

Gnomad SAS

AF:

0.887

Gnomad FIN

AF:

0.735

Gnomad MID

AF:

0.880

Gnomad NFE

AF:

0.781

Gnomad OTH

AF:

0.804

GnomAD3 exomes

AF:

0.818

AC:

203922

AN:

249190

Hom.:

84071

AF XY:

0.817

AC XY:

110532

AN XY:

135212

show subpopulations

Gnomad AFR exome

AF:

0.778

Gnomad AMR exome

AF:

0.906

Gnomad ASJ exome

AF:

0.789

Gnomad EAS exome

AF:

0.943

Gnomad SAS exome

AF:

0.877

Gnomad FIN exome

AF:

0.722

Gnomad NFE exome

AF:

0.783

Gnomad OTH exome

AF:

0.809

GnomAD4 exome

AF:

0.798

AC:

1165750

AN:

1461486

Hom.:

466520

Cov.:

AF XY:

0.800

AC XY:

581511

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.779

Gnomad4 AMR exome

AF:

0.900

Gnomad4 ASJ exome

AF:

0.789

Gnomad4 EAS exome

AF:

0.932

Gnomad4 SAS exome

AF:

0.877

Gnomad4 FIN exome

AF:

0.724

Gnomad4 NFE exome

AF:

0.786

Gnomad4 OTH exome

AF:

0.804

GnomAD4 genome

AF:

0.795

AC:

120808

AN:

151950

Hom.:

48238

Cov.:

AF XY:

0.796

AC XY:

59117

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.781

Gnomad4 AMR

AF:

0.853

Gnomad4 ASJ

AF:

0.782

Gnomad4 EAS

AF:

0.935

Gnomad4 SAS

AF:

0.887

Gnomad4 FIN

AF:

0.735

Gnomad4 NFE

AF:

0.781

Gnomad4 OTH

AF:

0.806

Alfa

AF:

0.796

Hom.:

75617

Bravo

AF:

0.803

TwinsUK

AF:

0.791

AC:

2933

ALSPAC

AF:

0.786

AC:

3029

ExAC

AF:

0.814

AC:

98384

Asia WGS

AF:

0.910

AC:

3165

AN:

3478

EpiCase

AF:

0.796

EpiControl

AF:

0.802

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 08, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Dec 11, 2014	This is a RefSeq error. The reference base (c.425G) is the minor allele. This al lele (G) has been identified in has been identified in 27% (1834/6748) of Finnis h chromosmes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs7349185) and thus meets criteria to be classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Eichsfeld type congenital muscular dystrophy

Benign:3

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	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 18, 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

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.32

DEOGEN2

Benign

0.054

.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0076

LIST_S2

Benign

0.11

T;T;T

MetaRNN

Benign

8.5e-7

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

.;L;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.44

PROVEAN

Benign

3.1

N;N;N

REVEL

Benign

0.043

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.054

MPC

0.39

ClinPred

0.00084

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

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