rs147131452

Variant names:

• chr1-25815590-G-A
• rs147131452
• NM_020451.3:c.1645G>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.1645G>A​(p.Val549Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,614,140 control chromosomes in the GnomAD database, including 14 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (12 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.78
• 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, 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=0.005793333).
• BP6: Variant 1-25815590-G-A is Benign according to our data. Variant chr1-25815590-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00267 (406/152278) while in subpopulation EAS AF = 0.0108 (56/5162). AF 95% confidence interval is 0.00858. There are 2 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.1645G>A	p.Val549Met	missense	Exon 13 of 13	NP_065184.2
	SELENON	NM_206926.2		c.1543G>A	p.Val515Met	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.1645G>A	p.Val549Met	missense	Exon 13 of 13	ENSP00000355141.2	Q9NZV5-1
	ENSG00000255054	ENST00000527604.1	TSL:5	n.123+1412G>A		intron	N/A	ENSP00000457066.1	H3BT81
	SELENON	ENST00000374315.1	TSL:5	c.1543G>A	p.Val515Met	missense	Exon 12 of 12	ENSP00000363434.1	Q9NZV5-2

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 403 AN: 152160 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00618

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00272 AC: 679 AN: 249548 AF XY: 0.00284

Gnomad AFR exome AF: 0.00626

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.0125

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.000874

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00116 AC: 1689 AN: 1461862 Hom.: 12 Cov.: 31 AF XY: 0.00124 AC XY: 905 AN XY: 727238

African (AFR) AF: 0.00684 AC: 229 AN: 33478

American (AMR) AF: 0.000358 AC: 16 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00383 AC: 100 AN: 26136

East Asian (EAS) AF: 0.0103 AC: 408 AN: 39700

South Asian (SAS) AF: 0.00502 AC: 433 AN: 86258

European-Finnish (FIN) AF: 0.00183 AC: 98 AN: 53412

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000260 AC: 289 AN: 1111994

Other (OTH) AF: 0.00184 AC: 111 AN: 60394

GnomAD4 genome AF: 0.00267 AC: 406 AN: 152278 Hom.: 2 Cov.: 33 AF XY: 0.00263 AC XY: 196 AN XY: 74466

African (AFR) AF: 0.00623 AC: 259 AN: 41562

American (AMR) AF: 0.000850 AC: 13 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5162

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4826

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68034

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00169 Hom.: 7

Bravo AF: 0.00318

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00587 AC: 24

ESP6500EA AF: 0.000358 AC: 3

ExAC AF: 0.00298 AC: 360

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Eichsfeld type congenital muscular dystrophy (1)
-	-	1	Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion (1)
-	-	1	SEPN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.061	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-1.8	N
PhyloP100		1.8
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.28
Sift	Benign	1.0	T
Sift4G	Benign	0.70	T
Polyphen		0.0030	B
Vest4		0.15
MVP		0.71
MPC		0.24
ClinPred		0.0021	T
GERP RS		-0.99
Varity_R		0.024
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs147131452; hg19: chr1-26142081;