NM_020451.3:c.425G>A

Variant names:

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

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, 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

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

Sel.	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	Q9NZV5-2

Ensembl Transcripts

Sel.	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	Q9NZV5-1
	SELENON	ENST00000374315.1	TSL:5	c.323G>A	p.Cys108Tyr	missense	Exon 3 of 12	ENSP00000363434.1	Q9NZV5-2
	SELENON	ENST00000354177.9	TSL:5	c.323G>A	p.Cys108Tyr	missense	Exon 3 of 12	ENSP00000346109.5	H9KV50

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	Eichsfeld type congenital muscular dystrophy (3)
-	-	2	not provided (2)
-	-	1	SEPN1-related disorder (1)

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;