rs797045950

Positions:

chr1-25809104-G-GCCT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4_SupportingPP3PP5_Very_Strong

The NM_020451.3(SELENON):c.827_829dup(p.Ala276_Cys277insSer) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SELENON
NM_020451.3 inframe_insertion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.77

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_020451.3. Strenght limited to Supporting due to length of the change: 1aa.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 1-25809104-G-GCCT is Pathogenic according to our data. Variant chr1-25809104-G-GCCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3 linkuse as main transcript	c.827_829dup	p.Ala276_Cys277insSer	inframe_insertion	6/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2 linkuse as main transcript	c.725_727dup	p.Ala242_Cys243insSer	inframe_insertion	5/12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7 linkuse as main transcript	c.827_829dup	p.Ala276_Cys277insSer	inframe_insertion	6/13	1	NM_020451.3	ENSP00000355141		Q9NZV5-1
SELENON	ENST00000354177.9 linkuse as main transcript	c.656_658dup	p.Ala219_Cys220insSer	inframe_insertion	5/12	5		ENSP00000346109
SELENON	ENST00000374315.1 linkuse as main transcript	c.725_727dup	p.Ala242_Cys243insSer	inframe_insertion	5/12	5		ENSP00000363434	P1	Q9NZV5-2
SELENON	ENST00000494537.2 linkuse as main transcript	c.725_727dup	p.Ala242_Cys243insSer	inframe_insertion, NMD_transcript_variant	5/13	3		ENSP00000508308

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249302

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461430

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727018

show subpopulations

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:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital myopathy 4A, autosomal dominant

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The inframe insertion variant c.827_829dup (p.Ala276_Cys277insSer) has been submitted to ClinVar as Likely Pathogenic. It has been reported previously using alternate nomenclature (c.829_829insTCC) in the homozygous state in an individual with significant neck extensor and flexor weakness, mild axial and limb girdle weakness, and developmental delay (Ardissone et al., 2016). This p.Ala276_Cys277insSer variant has allele frequency of 0.0008% in the gnomAD and novel (not in any individuals) in 1000 genome database . The insertion of amino acid Ser between amino acids Ala at position 276 and Cys at position 277 changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant , the molecular diagnosis is not confirmed. -

Congenital myopathy with fiber type disproportion

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 14, 2015

- -

Eichsfeld type congenital muscular dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 24, 2023

The p.Ala276_Cys277insSer variant in SELENON has been reported in 2 individuals with SELENON-RM (PMID: 30932294, 26780752) and has been identified in 0.007% (2/30600) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1329981323). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 212149) and has been interpreted as likely pathogenic by GeneDx and Genetic Services Laboratory (University of Chicago). Of the 2 affected individuals, both were homozygotes, which increases the likelihood that the p.Ala276_Cys277insSer variant is pathogenic (PMID: 30932294, 26780752). In vitro functional studies provide some evidence that the p.Ala276_Cys277insSer variant may impact protein function (PMID: 30932294). However, these types of assays may not accurately represent biological function. This variant is an insertion of 1 amino acid at position 276 and is not predicted to alter the protein reading-frame. This insertion is expected to impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive SELENON-RM. ACMG/AMP Criteria applied: PM3, PS3_moderate, PM2_supporting, PM4_supporting (Richards 2015). -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 11, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In-frame insertion of 1 amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 26780752, 30932294, 31069529) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over