1-25811844-C-T

Variant names:

• chr1-25811844-C-T
• rs369207232
• NM_020451.3:c.1246C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_020451.3(SELENON):​c.1246C>T​(p.Arg416Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000526 in 1,578,354 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R416Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000056 (1 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.97
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40076908).

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.1246C>T	p.Arg416Trp	missense	Exon 9 of 13	NP_065184.2
	SELENON	NM_206926.2		c.1144C>T	p.Arg382Trp	missense	Exon 8 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.1246C>T	p.Arg416Trp	missense	Exon 9 of 13	ENSP00000355141.2	Q9NZV5-1
	SELENON	ENST00000374315.1	TSL:5	c.1144C>T	p.Arg382Trp	missense	Exon 8 of 12	ENSP00000363434.1	Q9NZV5-2
	SELENON	ENST00000354177.9	TSL:5	c.1075C>T	p.Arg359Trp	missense	Exon 8 of 12	ENSP00000346109.5	H9KV50

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000904 AC: 17 AN: 188008 AF XY: 0.0000791

Gnomad AFR exome AF: 0.0000943

Gnomad AMR exome AF: 0.0000360

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000750

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000561 AC: 80 AN: 1426056 Hom.: 1 Cov.: 37 AF XY: 0.0000623 AC XY: 44 AN XY: 706074

African (AFR) AF: 0.0000304 AC: 1 AN: 32916

American (AMR) AF: 0.0000257 AC: 1 AN: 38952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25462

East Asian (EAS) AF: 0.00 AC: 0 AN: 38106

South Asian (SAS) AF: 0.000319 AC: 26 AN: 81576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50734

Middle Eastern (MID) AF: 0.000193 AC: 1 AN: 5182

European-Non Finnish (NFE) AF: 0.0000439 AC: 48 AN: 1094156

Other (OTH) AF: 0.0000509 AC: 3 AN: 58972

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152298 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74462

African (AFR) AF: 0.0000481 AC: 2 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.000239 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000754 AC: 9

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Eichsfeld type congenital muscular dystrophy (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.7	L
PhyloP100		2.0
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.52
MVP		0.97
MPC		0.25
ClinPred		0.28	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
Mutation Taster		=78/22	polymorphism

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: rs369207232; hg19: chr1-26138335;