rs148071754

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020451.3(SELENON):c.1092+6C>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00982 in 1,613,672 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 13 hom., cov: 33)

Exomes 𝑓: 0.010 ( 107 hom. )

Consequence

SELENON
NM_020451.3 splice_donor_region, intron

Scores

Splicing: ADA: 0.00003976

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.0720

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 1-25811541-C-G is Benign according to our data. Variant chr1-25811541-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 212146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25811541-C-G is described in Lovd as [Benign]. Variant chr1-25811541-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00732 (1115/152296) while in subpopulation NFE AF= 0.0123 (836/68024). AF 95% confidence interval is 0.0116. There are 13 homozygotes in gnomad4. There are 520 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3 linkuse as main transcript	c.1092+6C>G		splice_donor_region_variant, intron_variant		ENST00000361547.7
SELENON	NM_206926.2 linkuse as main transcript	c.990+6C>G		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7 linkuse as main transcript	c.1092+6C>G	splice_donor_region_variant, intron_variant	1	NM_020451.3		Q9NZV5-1
SELENON	ENST00000354177.9 linkuse as main transcript	c.921+6C>G	splice_donor_region_variant, intron_variant	5
SELENON	ENST00000374315.1 linkuse as main transcript	c.990+6C>G	splice_donor_region_variant, intron_variant	5		P1	Q9NZV5-2
SELENON	ENST00000494537.2 linkuse as main transcript	c.990+6C>G	splice_donor_region_variant, intron_variant, NMD_transcript_variant	3

Frequencies

GnomAD3 genomes

AF:

0.00733

AC:

1115

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00641

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00775

AC:

1934

AN:

249452

Hom.:

AF XY:

0.00811

AC XY:

1098

AN XY:

135342

show subpopulations

Gnomad AFR exome

AF:

0.00207

Gnomad AMR exome

AF:

0.00437

Gnomad ASJ exome

AF:

0.00765

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00556

Gnomad FIN exome

AF:

0.00359

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.0101

AC:

14739

AN:

1461376

Hom.:

107

Cov.:

AF XY:

0.0102

AC XY:

7393

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.00197

Gnomad4 AMR exome

AF:

0.00452

Gnomad4 ASJ exome

AF:

0.00666

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00608

Gnomad4 FIN exome

AF:

0.00414

Gnomad4 NFE exome

AF:

0.0116

Gnomad4 OTH exome

AF:

0.00908

GnomAD4 genome

AF:

0.00732

AC:

1115

AN:

152296

Hom.:

Cov.:

AF XY:

0.00698

AC XY:

520

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00188

Gnomad4 AMR

AF:

0.00542

Gnomad4 ASJ

AF:

0.00807

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00642

Gnomad4 FIN

AF:

0.00311

Gnomad4 NFE

AF:

0.0123

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.00806

Hom.:

Bravo

AF:

0.00724

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0141

EpiControl

AF:

0.0134

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 18, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 05, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SELENON: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

SEPN1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Eichsfeld type congenital muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

Cadd

Benign

2.4

Dann

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000040

dbscSNV1_RF

Benign

0.026

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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