rs199911454

Positions:

chr1-25815568-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7

The NM_020451.3(SELENON):c.1623C>T(p.Asn541=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000764 in 1,614,196 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00077 ( 1 hom. )

Consequence

SELENON
NM_020451.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.16

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 1-25815568-C-T is Benign according to our data. Variant chr1-25815568-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 297030.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr1-25815568-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=2.16 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3 linkuse as main transcript	c.1623C>T	p.Asn541=	synonymous_variant	13/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2 linkuse as main transcript	c.1521C>T	p.Asn507=	synonymous_variant	12/12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7 linkuse as main transcript	c.1623C>T	p.Asn541=	synonymous_variant	13/13	1	NM_020451.3	ENSP00000355141		Q9NZV5-1
SELENON	ENST00000374315.1 linkuse as main transcript	c.1521C>T	p.Asn507=	synonymous_variant	12/12	5		ENSP00000363434	P1	Q9NZV5-2
SELENON	ENST00000354177.9 linkuse as main transcript	c.1452C>T	p.Asn484=	synonymous_variant	12/12	5		ENSP00000346109
SELENON	ENST00000494537.2 linkuse as main transcript	c.*143C>T		3_prime_UTR_variant, NMD_transcript_variant	13/13	3		ENSP00000508308

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000955

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000553

AC:

138

AN:

249532

Hom.:

AF XY:

0.000524

AC XY:

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000580

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000743

Gnomad NFE exome

AF:

0.000724

Gnomad OTH exome

AF:

0.000825

GnomAD4 exome

AF:

0.000772

AC:

1129

AN:

1461838

Hom.:

Cov.:

AF XY:

0.000723

AC XY:

526

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.000599

Gnomad4 NFE exome

AF:

0.000896

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000683

AC:

104

AN:

152358

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000979

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.000955

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000753

Hom.:

Bravo

AF:

0.000593

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2022	Variant summary: SELENON c.1623C>T alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00055 in 249532 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SELENON causing Eichsfeld Type Congenital Muscular Dystrophy (0.00055 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1623C>T in individuals affected with Eichsfeld Type Congenital Muscular Dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified the variant as likely benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2017	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. -

SEPN1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Eichsfeld type congenital muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

8.5

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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