rs74060854

Positions:

• chr1-25815690-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000361547.7(SELENON):​c.1745G>A​(p.Arg582Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,614,058 control chromosomes in the GnomAD database, including 246 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 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. R582W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (131 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (115 hom.)
• Consequence: SELENON ENST00000361547.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.12

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002723366).
• BP6: Variant 1-25815690-G-A is Benign according to our data. Variant chr1-25815690-G-A is described in ClinVar as [Benign]. Clinvar id is 261280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25815690-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3	c.1745G>A	p.Arg582Gln	missense_variant	13/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.1643G>A	p.Arg548Gln	missense_variant	12/12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.1745G>A	p.Arg582Gln	missense_variant	13/13	1	NM_020451.3	ENSP00000355141
SELENON	ENST00000374315.1	c.1643G>A	p.Arg548Gln	missense_variant	12/12	5		ENSP00000363434	P1
SELENON	ENST00000354177.9	c.1574G>A	p.Arg525Gln	missense_variant	12/12	5		ENSP00000346109
SELENON	ENST00000494537.2	c.*265G>A		3_prime_UTR_variant, NMD_transcript_variant	13/13	3		ENSP00000508308

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3325 AN: 152158 Hom.: 131 Cov.: 33

Gnomad AFR AF: 0.0757

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00799

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00567 AC: 1413 AN: 249410 Hom.: 68 AF XY: 0.00404 AC XY: 547 AN XY: 135338

Gnomad AFR exome AF: 0.0783

Gnomad AMR exome AF: 0.00388

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00242 AC: 3534 AN: 1461782 Hom.: 115 Cov.: 31 AF XY: 0.00207 AC XY: 1505 AN XY: 727200

Gnomad4 AFR exome AF: 0.0764

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000359

Gnomad4 OTH exome AF: 0.00528

GnomAD4 genome AF: 0.0219 AC: 3342 AN: 152276 Hom.: 131 Cov.: 33 AF XY: 0.0211 AC XY: 1569 AN XY: 74462

Gnomad4 AFR AF: 0.0759

Gnomad4 AMR AF: 0.00798

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00478 Hom.: 37

Bravo AF: 0.0250

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0671 AC: 273

ESP6500EA AF: 0.000478 AC: 4

ExAC AF: 0.00690 AC: 835

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 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. -

SEPN1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Eichsfeld type congenital muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.044	.;T;.;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.70	T;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;N;.;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.60	N;N;N;.
REVEL	Benign	0.12
Sift	Benign	0.19	T;T;T;.
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.0090, 0.015	.;B;B;.
Vest4		0.14
MVP		0.79
MPC		0.27
ClinPred		0.0061	T
GERP RS		0.70
Varity_R		0.020

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

Other links and lift over

dbSNP: rs74060854; hg19: chr1-26142181;