rs200128474

Positions:

chr1-25815599-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_020451.3(SELENON):c.1654G>A(p.Glu552Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,614,184 control chromosomes in the GnomAD database, including 4 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 0.00038 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 4 hom. )

Consequence

SELENON
NM_020451.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 9.38

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22595707).

BP6

Variant 1-25815599-G-A is Benign according to our data. Variant chr1-25815599-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95961.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=7}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00034 (497/1461874) while in subpopulation MID AF= 0.0114 (66/5768). AF 95% confidence interval is 0.00923. There are 4 homozygotes in gnomad4_exome. There are 260 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3 linkuse as main transcript	c.1654G>A	p.Glu552Lys	missense_variant	13/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2 linkuse as main transcript	c.1552G>A	p.Glu518Lys	missense_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.1654G>A	p.Glu552Lys	missense_variant	13/13	1	NM_020451.3	ENSP00000355141		Q9NZV5-1
SELENON	ENST00000374315.1 linkuse as main transcript	c.1552G>A	p.Glu518Lys	missense_variant	12/12	5		ENSP00000363434	P1	Q9NZV5-2
SELENON	ENST00000354177.9 linkuse as main transcript	c.1483G>A	p.Glu495Lys	missense_variant	12/12	5		ENSP00000346109
SELENON	ENST00000494537.2 linkuse as main transcript	c.*174G>A		3_prime_UTR_variant, NMD_transcript_variant	13/13	3		ENSP00000508308

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.000377

AC:

AN:

249566

Hom.:

AF XY:

0.000451

AC XY:

AN XY:

135398

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.000666

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000406

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.000340

AC:

497

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000358

AC XY:

260

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.000827

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000371

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000260

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000381

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000468

Hom.:

Bravo

AF:

0.000423

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000245

AC:

ESP6500EA

AF:

0.000477

AC:

ExAC

AF:

0.000355

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2021	This variant is associated with the following publications: (PMID: 20623375) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 18, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 12, 2021	- -

Eichsfeld type congenital muscular dystrophy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 16, 2023

Variant summary: SELENON c.1654G>A (p.Glu552Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 249566 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SELENON causing Eichsfeld Type Congenital Muscular Dystrophy (0.00038 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1654G>A in individuals affected with Eichsfeld Type Congenital Muscular Dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=2) and benign/likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Congenital myopathy with fiber type disproportion

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 13, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

SEPN1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

.;T;.;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.76

T;T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.8

.;L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.95

N;N;N;.

REVEL

Pathogenic

0.67

Sift

Uncertain

0.024

D;D;D;.

Sift4G

Uncertain

0.060

T;T;T;T

Polyphen

1.0, 0.99

.;D;D;.

Vest4

0.52

MVP

0.97

MPC

0.42

ClinPred

0.11

GERP RS

4.9

Varity_R

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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