rs115852080

Variant names:

• chr1-25808625-G-A
• rs115852080
• NM_020451.3:c.583G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020451.3(SELENON):​c.583G>A​(p.Ala195Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,613,668 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 33)
  • Exomes 𝑓: 0.013 (166 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.25
• Publications: 10 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=0.004422933).
• BP6: Variant 1-25808625-G-A is Benign according to our data. Variant chr1-25808625-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95966.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 = 0.0106 (1611/152086) while in subpopulation NFE AF = 0.015 (1017/67920). AF 95% confidence interval is 0.0142. There are 28 homozygotes in GnomAd4. There are 711 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3	c.583G>A	p.Ala195Thr	missense_variant	Exon 5 of 13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.481G>A	p.Ala161Thr	missense_variant	Exon 4 of 12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.583G>A	p.Ala195Thr	missense_variant	Exon 5 of 13	1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1	c.481G>A	p.Ala161Thr	missense_variant	Exon 4 of 12	5		ENSP00000363434.1
SELENON	ENST00000354177.9	c.481G>A	p.Ala161Thr	missense_variant	Exon 4 of 12	5		ENSP00000346109.5
SELENON	ENST00000494537.2	n.481G>A		non_coding_transcript_exon_variant	Exon 4 of 13	3		ENSP00000508308.1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1610 AN: 151968 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.00464

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0101 AC: 2498 AN: 248090 AF XY: 0.0106

Gnomad AFR exome AF: 0.00498

Gnomad AMR exome AF: 0.00742

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00266

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0141

GnomAD4 exome AF: 0.0133 AC: 19496 AN: 1461582 Hom.: 166 Cov.: 32 AF XY: 0.0134 AC XY: 9765 AN XY: 727110

African (AFR) AF: 0.00523 AC: 175 AN: 33478

American (AMR) AF: 0.00787 AC: 352 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 281 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00920 AC: 794 AN: 86258

European-Finnish (FIN) AF: 0.00250 AC: 133 AN: 53178

Middle Eastern (MID) AF: 0.0150 AC: 86 AN: 5752

European-Non Finnish (NFE) AF: 0.0152 AC: 16883 AN: 1111972

Other (OTH) AF: 0.0131 AC: 789 AN: 60392

GnomAD4 genome AF: 0.0106 AC: 1611 AN: 152086 Hom.: 28 Cov.: 33 AF XY: 0.00956 AC XY: 711 AN XY: 74348

African (AFR) AF: 0.00465 AC: 193 AN: 41488

American (AMR) AF: 0.00883 AC: 135 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4824

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10604

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0150 AC: 1017 AN: 67920

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.0133 Hom.: 26

Bravo AF: 0.0114

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00510 AC: 21

ESP6500EA AF: 0.0155 AC: 130

ExAC AF: 0.00999 AC: 1208

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0176

EpiControl AF: 0.0165

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala195Thr in exon 5 of SEPN1: This variant is not expected to have clinical significance because it has been identified in 1.4% (907/66106) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs115852080). -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Sep 07, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 13, 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:5

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SELENON: BP4, BS1, BS2 -

Oct 10, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

SEPN1-related disorder Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Eichsfeld type congenital muscular dystrophy Benign:1

Feb 03, 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_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	.;T;.
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.044
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	0.0044	T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.1	.;L;.
PhyloP100		3.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.059	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.95, 0.97	.;P;D
Vest4		0.34
MVP		0.92
MPC		0.28
ClinPred		0.015	T
GERP RS		4.0
Varity_R		0.056
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs115852080; hg19: chr1-26135116; COSMIC: COSV99052738; COSMIC: COSV99052738;