1-25800232-T-TGGGCCGGGCC

Variant names:

• chr1-25800232-T-TGGGCCGGGCC
• rs1572226744
• NM_020451.3:c.3_12dupGGGCCGGGCC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_020451.3(SELENON):​c.3_12dupGGGCCGGGCC​(p.Arg5GlyfsTer81) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 628,544 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SELENON NM_020451.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.342

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 144 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3	c.3_12dupGGGCCGGGCC	p.Arg5GlyfsTer81	frameshift_variant	Exon 1 of 13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.3_12dupGGGCCGGGCC	p.Arg5GlyfsTer81	frameshift_variant	Exon 1 of 12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.3_12dupGGGCCGGGCC	p.Arg5GlyfsTer81	frameshift_variant	Exon 1 of 13	1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1	c.3_12dupGGGCCGGGCC	p.Arg5GlyfsTer81	frameshift_variant	Exon 1 of 12	5		ENSP00000363434.1
SELENON	ENST00000354177.9	c.3_12dupGGGCCGGGCC	p.Arg5GlyfsTer81	frameshift_variant	Exon 1 of 12	5		ENSP00000346109.5
SELENON	ENST00000494537.2	n.3_12dupGGGCCGGGCC		non_coding_transcript_exon_variant	Exon 1 of 13	3		ENSP00000508308.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000111 AC: 7 AN: 628544 Hom.: 0 Cov.: 8 AF XY: 0.00000342 AC XY: 1 AN XY: 292422

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000122

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1572226744; hg19: chr1-26126723;