rs74060854

Variant names:

• chr1-25815690-G-A
• rs74060854
• NM_020451.3:c.1745G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-25815690-G-A
• chr1-25815690-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.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. 16/20 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. R582W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (131 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (115 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.12
• Publications: 4 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, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics
• 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

ENSG00000255054 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0737 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	NM_020451.3	MANE Select	c.1745G>A	p.Arg582Gln	missense	Exon 13 of 13	NP_065184.2
	SELENON	NM_206926.2		c.1643G>A	p.Arg548Gln	missense	Exon 12 of 12	NP_996809.1	Q9NZV5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	ENST00000361547.7	TSL:1 MANE Select	c.1745G>A	p.Arg582Gln	missense	Exon 13 of 13	ENSP00000355141.2	Q9NZV5-1
	ENSG00000255054	ENST00000527604.1	TSL:5	n.123+1512G>A		intron	N/A	ENSP00000457066.1	H3BT81
	SELENON	ENST00000374315.1	TSL:5	c.1643G>A	p.Arg548Gln	missense	Exon 12 of 12	ENSP00000363434.1	Q9NZV5-2

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

GnomAD2 exomes AF: 0.00567 AC: 1413 AN: 249410 AF XY: 0.00404

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 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

African (AFR) AF: 0.0764 AC: 2557 AN: 33480

American (AMR) AF: 0.00443 AC: 198 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5766

European-Non Finnish (NFE) AF: 0.000359 AC: 399 AN: 1111998

Other (OTH) AF: 0.00528 AC: 319 AN: 60394

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

African (AFR) AF: 0.0759 AC: 3154 AN: 41544

American (AMR) AF: 0.00798 AC: 122 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68028

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

Alfa AF: 0.00851 Hom.: 97

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Eichsfeld type congenital muscular dystrophy (1)
-	-	1	not provided (1)
-	-	1	SEPN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.1
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.60	N
REVEL	Benign	0.12
Sift	Benign	0.19	T
Sift4G	Benign	0.45	T
Polyphen		0.0090	B
Vest4		0.14
MVP		0.79
MPC		0.27
ClinPred		0.0061	T
GERP RS		0.70
Varity_R		0.020
Mutation Taster		=98/2	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: rs74060854; hg19: chr1-26142181;