NM_020451.3:c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC

Variant names:

• chr1-25800211-AGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGC-A
• rs1557813850
• NM_020451.3:c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PP5_Very_Strong

The NM_020451.3(SELENON):​c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 142,352 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SELENON NM_020451.3 frameshift, start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.792
• Publications: 1 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

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 93 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_020451.3 (SELENON) was described as [Likely_pathogenic] in ClinVar
• PP5: Variant 1-25800211-AGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGC-A is Pathogenic according to our data. Variant chr1-25800211-AGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 373075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC	p.Met1fs	frameshift start_lost	Exon 1 of 13	NP_065184.2
	SELENON	NM_020451.3	MANE Select	c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC		5_prime_UTR	Exon 1 of 13	NP_065184.2
	SELENON	NM_206926.2		c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC	p.Met1fs	frameshift start_lost	Exon 1 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.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC	p.Met1fs	frameshift start_lost	Exon 1 of 13	ENSP00000355141.2	Q9NZV5-1
	SELENON	ENST00000361547.7	TSL:1 MANE Select	c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC		5_prime_UTR	Exon 1 of 13	ENSP00000355141.2	Q9NZV5-1
	SELENON	ENST00000374315.1	TSL:5	c.-11_81delCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCGCGCCACCGCGCCGCCGC	p.Met1fs	frameshift start_lost	Exon 1 of 12	ENSP00000363434.1	Q9NZV5-2

Frequencies

GnomAD3 genomes AF: 0.0000140 AC: 2 AN: 142352 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000155

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000174 AC: 6 AN: 344628 Hom.: 0 AF XY: 0.00000621 AC XY: 1 AN XY: 160964

African (AFR) AF: 0.00 AC: 0 AN: 6664

American (AMR) AF: 0.00 AC: 0 AN: 412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2104

East Asian (EAS) AF: 0.00 AC: 0 AN: 1466

South Asian (SAS) AF: 0.00 AC: 0 AN: 7310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 692

European-Non Finnish (NFE) AF: 0.0000159 AC: 5 AN: 314460

Other (OTH) AF: 0.0000877 AC: 1 AN: 11400

GnomAD4 genome AF: 0.0000140 AC: 2 AN: 142352 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 69086

African (AFR) AF: 0.0000253 AC: 1 AN: 39594

American (AMR) AF: 0.00 AC: 0 AN: 14444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3344

East Asian (EAS) AF: 0.00 AC: 0 AN: 4848

South Asian (SAS) AF: 0.00 AC: 0 AN: 4560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000155 AC: 1 AN: 64612

Other (OTH) AF: 0.00 AC: 0 AN: 1988

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Eichsfeld type congenital muscular dystrophy (5)
1	-	-	Congenital myopathy with fiber type disproportion (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.79
Mutation Taster		=32/168	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1557813850; hg19: chr1-26126702;