rs2072749

Positions:

• chr1-25804530-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
SELENON	NM_020451.3	c.404-612T>C		intron_variant		ENST00000361547.7
SELENON	NM_206926.2	c.302-612T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7	c.404-612T>C		intron_variant		1	NM_020451.3
SELENON	ENST00000354177.9	c.302-612T>C		intron_variant		5
SELENON	ENST00000374315.1	c.302-612T>C		intron_variant		5		P1
SELENON	ENST00000494537.2	c.302-612T>C		intron_variant, NMD_transcript_variant		3

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

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.325

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.255

Alfa AF: 0.261 Hom.: 7489

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2072749; hg19: chr1-26131021;