rs141295085

Positions:

chr1-25805164-C-CGAG

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM4_SupportingPP3BP6BS1BS2

The NM_020451.3(SELENON):c.436_438dup(p.Glu146dup) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,608,570 control chromosomes in the GnomAD database, including 34 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0074 ( 21 hom., cov: 31)

Exomes 𝑓: 0.00076 ( 13 hom. )

Consequence

SELENON
NM_020451.3 inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 7.86

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 Benign. Variant got -7 ACMG points.

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

BP6

Variant 1-25805164-C-CGAG is Benign according to our data. Variant chr1-25805164-C-CGAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95965.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00738 (1124/152246) while in subpopulation AFR AF= 0.0259 (1075/41524). AF 95% confidence interval is 0.0246. There are 21 homozygotes in gnomad4. There are 522 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3 linkuse as main transcript	c.436_438dup	p.Glu146dup	inframe_insertion	4/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2 linkuse as main transcript	c.334_336dup	p.Glu112dup	inframe_insertion	3/12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7 linkuse as main transcript	c.436_438dup	p.Glu146dup	inframe_insertion	4/13	1	NM_020451.3	ENSP00000355141		Q9NZV5-1
SELENON	ENST00000354177.9 linkuse as main transcript	c.334_336dup	p.Glu112dup	inframe_insertion	3/12	5		ENSP00000346109
SELENON	ENST00000374315.1 linkuse as main transcript	c.334_336dup	p.Glu112dup	inframe_insertion	3/12	5		ENSP00000363434	P1	Q9NZV5-2
SELENON	ENST00000494537.2 linkuse as main transcript	c.334_336dup	p.Glu112dup	inframe_insertion, NMD_transcript_variant	3/13	3		ENSP00000508308

Frequencies

GnomAD3 genomes

AF:

0.00739

AC:

1124

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0260

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

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:

0.0000588

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00190

AC:

474

AN:

249206

Hom.:

AF XY:

0.00155

AC XY:

210

AN XY:

135222

show subpopulations

Gnomad AFR exome

AF:

0.0265

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000762

AC:

1109

AN:

1456324

Hom.:

Cov.:

AF XY:

0.000634

AC XY:

459

AN XY:

724404

show subpopulations

Gnomad4 AFR exome

AF:

0.0274

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00148

GnomAD4 genome

AF:

0.00738

AC:

1124

AN:

152246

Hom.:

Cov.:

AF XY:

0.00701

AC XY:

522

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0259

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00412

Hom.:

Bravo

AF:

0.00912

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 08, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 06, 2015	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2017	- -

Eichsfeld type congenital muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

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