rs2072749

Variant names:

• chr1-25804530-T-C
• rs2072749
• NM_020451.3:c.404-612T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020451.3(SELENON):​c.404-612T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 151,174 control chromosomes in the GnomAD database, including 4,149 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4149 hom., cov: 27)
• Consequence: SELENON NM_020451.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.686
• Publications: 8 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 Submitted by: Ambry Genetics, G2P
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3	c.404-612T>C		intron_variant	Intron 3 of 12	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.302-612T>C		intron_variant	Intron 2 of 11		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.404-612T>C		intron_variant	Intron 3 of 12	1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1	c.302-612T>C		intron_variant	Intron 2 of 11	5		ENSP00000363434.1
SELENON	ENST00000354177.9	c.302-612T>C		intron_variant	Intron 2 of 11	5		ENSP00000346109.5
SELENON	ENST00000494537.2	n.302-612T>C		intron_variant	Intron 2 of 12	3		ENSP00000508308.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 34835 AN: 151062 Hom.: 4144 Cov.: 27

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.254

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.231 AC: 34859 AN: 151174 Hom.: 4149 Cov.: 27 AF XY: 0.228 AC XY: 16837 AN XY: 73796

African (AFR) AF: 0.179 AC: 7364 AN: 41130

American (AMR) AF: 0.207 AC: 3147 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1132 AN: 3454

East Asian (EAS) AF: 0.325 AC: 1660 AN: 5108

South Asian (SAS) AF: 0.174 AC: 831 AN: 4786

European-Finnish (FIN) AF: 0.245 AC: 2543 AN: 10380

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17233 AN: 67836

Other (OTH) AF: 0.255 AC: 536 AN: 2100

Alfa AF: 0.257 Hom.: 8793

Bravo AF: 0.234

Asia WGS AF: 0.233 AC: 809 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.58
PhyloP100		-0.69
Mutation Taster		=100/0	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: rs2072749; hg19: chr1-26131021;