rs147131452

Positions:

• chr1-25815590-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020451.3(SELENON):​c.1645G>A​(p.Val549Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,614,140 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (12 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.78

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005793333).
• BP6: Variant 1-25815590-G-A is Benign according to our data. Variant chr1-25815590-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00267 (406/152278) while in subpopulation EAS AF= 0.0108 (56/5162). AF 95% confidence interval is 0.00858. There are 2 homozygotes in gnomad4. There are 196 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3	c.1645G>A	p.Val549Met	missense_variant	13/13	ENST00000361547.7
SELENON	NM_206926.2	c.1543G>A	p.Val515Met	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7	c.1645G>A	p.Val549Met	missense_variant	13/13	1	NM_020451.3
SELENON	ENST00000374315.1	c.1543G>A	p.Val515Met	missense_variant	12/12	5		P1
SELENON	ENST00000354177.9	c.1474G>A	p.Val492Met	missense_variant	12/12	5
SELENON	ENST00000494537.2	c.*165G>A		3_prime_UTR_variant, NMD_transcript_variant	13/13	3

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 403 AN: 152160 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00618

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00272 AC: 679 AN: 249548 Hom.: 5 AF XY: 0.00284 AC XY: 384 AN XY: 135394

Gnomad AFR exome AF: 0.00626

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.0125

Gnomad SAS exome AF: 0.00507

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.000874

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00116 AC: 1689 AN: 1461862 Hom.: 12 Cov.: 31 AF XY: 0.00124 AC XY: 905 AN XY: 727238

Gnomad4 AFR exome AF: 0.00684

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00383

Gnomad4 EAS exome AF: 0.0103

Gnomad4 SAS exome AF: 0.00502

Gnomad4 FIN exome AF: 0.00183

Gnomad4 NFE exome AF: 0.000260

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00267 AC: 406 AN: 152278 Hom.: 2 Cov.: 33 AF XY: 0.00263 AC XY: 196 AN XY: 74466

Gnomad4 AFR AF: 0.00623

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00139 Hom.: 4

Bravo AF: 0.00318

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00587 AC: 24

ESP6500EA AF: 0.000358 AC: 3

ExAC AF: 0.00298 AC: 360

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2019	This variant is associated with the following publications: (PMID: 22426012) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SELENON: BP4, BS1 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.061	.;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.39	T;T;T;T
MetaRNN	Benign	0.0058	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-1.8	.;N;.;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.67	N;N;N;.
REVEL	Benign	0.28
Sift	Benign	1.0	T;T;T;.
Sift4G	Benign	0.70	T;T;T;T
Polyphen		0.0030, 0.0050	.;B;B;.
Vest4		0.15
MVP		0.71
MPC		0.24
ClinPred		0.0021	T
GERP RS		-0.99
Varity_R		0.024

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

Other links and lift over

dbSNP: rs147131452; hg19: chr1-26142081;