rs7349185

Variant names:

• chr1-25805163-G-A
• rs7349185
• NM_020451.3:c.425G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-25805163-G-A
• chr1-25805163-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/20 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. C142S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.80 (48238 hom., cov: 30)
  • Exomes 𝑓: 0.80 (466520 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.869
• Publications: 37 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 95963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020451.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	NM_020451.3	MANE Select	c.425G>A	p.Cys142Tyr	missense	Exon 4 of 13	NP_065184.2
	SELENON	NM_206926.2		c.323G>A	p.Cys108Tyr	missense	Exon 3 of 12	NP_996809.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	ENST00000361547.7	TSL:1 MANE Select	c.425G>A	p.Cys142Tyr	missense	Exon 4 of 13	ENSP00000355141.2
	SELENON	ENST00000374315.1	TSL:5	c.323G>A	p.Cys108Tyr	missense	Exon 3 of 12	ENSP00000363434.1
	SELENON	ENST00000354177.9	TSL:5	c.323G>A	p.Cys108Tyr	missense	Exon 3 of 12	ENSP00000346109.5

Frequencies

GnomAD3 genomes AF: 0.795 AC: 120726 AN: 151832 Hom.: 48208 Cov.: 30

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

GnomAD2 exomes AF: 0.818 AC: 203922 AN: 249190 AF XY: 0.817

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 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.: 63 AF XY: 0.800 AC XY: 581511 AN XY: 727024

African (AFR) AF: 0.779 AC: 26080 AN: 33470

American (AMR) AF: 0.900 AC: 40263 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.789 AC: 20611 AN: 26136

East Asian (EAS) AF: 0.932 AC: 37006 AN: 39700

South Asian (SAS) AF: 0.877 AC: 75614 AN: 86248

European-Finnish (FIN) AF: 0.724 AC: 38525 AN: 53194

Middle Eastern (MID) AF: 0.853 AC: 4848 AN: 5684

European-Non Finnish (NFE) AF: 0.786 AC: 874280 AN: 1111954

Other (OTH) AF: 0.804 AC: 48523 AN: 60376

GnomAD4 genome AF: 0.795 AC: 120808 AN: 151950 Hom.: 48238 Cov.: 30 AF XY: 0.796 AC XY: 59117 AN XY: 74266

African (AFR) AF: 0.781 AC: 32304 AN: 41380

American (AMR) AF: 0.853 AC: 13026 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 2713 AN: 3468

East Asian (EAS) AF: 0.935 AC: 4828 AN: 5164

South Asian (SAS) AF: 0.887 AC: 4259 AN: 4804

European-Finnish (FIN) AF: 0.735 AC: 7777 AN: 10584

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.781 AC: 53068 AN: 67972

Other (OTH) AF: 0.806 AC: 1699 AN: 2108

Alfa AF: 0.792 Hom.: 149203

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

Submissions by phenotype

not specified Benign:8

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 08, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 11, 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.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.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Eichsfeld type congenital muscular dystrophy Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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 18, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SEPN1-related disorder Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.32
DEOGEN2	Benign	0.054	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0076	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	8.5e-7	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.87
PrimateAI	Benign	0.44	T
PROVEAN	Benign	3.1	N
REVEL	Benign	0.043
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.054
MPC		0.39
ClinPred		0.00084	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7349185; hg19: chr1-26131654; COSMIC: COSV62525203;