1-25800232-T-TGGGCC

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_020451.3(SELENON):c.8_12dup(p.Arg5_?4) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: SELENON NM_020451.3 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 20 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 150 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_020451.3 (SELENON) was described as [Likely_pathogenic] in ClinVar as 4491
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-25800232-T-TGGGCC is Pathogenic according to our data. Variant chr1-25800232-T-TGGGCC is described in ClinVar as [Pathogenic]. Clinvar id is 623320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3	c.8_12dup	p.Arg5_?4	frameshift_variant, start_lost	1/13	ENST00000361547.7
SELENON	NM_206926.2	c.8_12dup	p.Arg5_?4	frameshift_variant, start_lost	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7	c.8_12dup	p.Arg5_?4	frameshift_variant, start_lost	1/13	1	NM_020451.3
SELENON	ENST00000354177.9	c.8_12dup	p.Arg5_?4	frameshift_variant, start_lost	1/12	5
SELENON	ENST00000374315.1	c.8_12dup	p.Arg5_?4	frameshift_variant, start_lost	1/12	5		P1
SELENON	ENST00000494537.2	c.8_12dup	p.Arg5_?4	frameshift_variant, start_lost, NMD_transcript_variant	1/13	3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 8

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 07, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 623320). This premature translational stop signal has been observed in individual(s) with SELENON-related conditions (PMID: 19557870). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg5Glyfs*63) in the SELENON gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SELENON are known to be pathogenic (PMID: 21131290, 21670436). -
Pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 20, 2023	- -

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;