1-25811771-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020451.3(SELENON):c.1173T>C(p.Pro391=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.79 in 1,592,998 control chromosomes in the GnomAD database, including 499,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43500 hom., cov: 34)
  • Exomes 𝑓: 0.79 (456466 hom.)
• Consequence: SELENON NM_020451.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.302

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-25811771-T-C is Benign according to our data. Variant chr1-25811771-T-C is described in ClinVar as [Benign]. Clinvar id is 95956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25811771-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.302 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3	c.1173T>C	p.Pro391=	synonymous_variant	9/13	ENST00000361547.7
SELENON	NM_206926.2	c.1071T>C	p.Pro357=	synonymous_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7	c.1173T>C	p.Pro391=	synonymous_variant	9/13	1	NM_020451.3
SELENON	ENST00000374315.1	c.1071T>C	p.Pro357=	synonymous_variant	8/12	5		P1
SELENON	ENST00000354177.9	c.1002T>C	p.Pro334=	synonymous_variant	8/12	5
SELENON	ENST00000494537.2	c.1071T>C	p.Pro357=	synonymous_variant, NMD_transcript_variant	8/13	3

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113974 AN: 152086 Hom.: 43465 Cov.: 34

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.939

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.966

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.759

GnomAD3 exomes AF: 0.810 AC: 171867 AN: 212212 Hom.: 70251 AF XY: 0.812 AC XY: 93414 AN XY: 115030

Gnomad AFR exome AF: 0.607

Gnomad AMR exome AF: 0.891

Gnomad ASJ exome AF: 0.771

Gnomad EAS exome AF: 0.965

Gnomad SAS exome AF: 0.877

Gnomad FIN exome AF: 0.741

Gnomad NFE exome AF: 0.784

Gnomad OTH exome AF: 0.811

GnomAD4 exome AF: 0.794 AC: 1144177 AN: 1440794 Hom.: 456466 Cov.: 61 AF XY: 0.797 AC XY: 569704 AN XY: 714946

Gnomad4 AFR exome AF: 0.606

Gnomad4 AMR exome AF: 0.884

Gnomad4 ASJ exome AF: 0.770

Gnomad4 EAS exome AF: 0.960

Gnomad4 SAS exome AF: 0.878

Gnomad4 FIN exome AF: 0.744

Gnomad4 NFE exome AF: 0.787

Gnomad4 OTH exome AF: 0.794

GnomAD4 genome AF: 0.749 AC: 114063 AN: 152204 Hom.: 43500 Cov.: 34 AF XY: 0.753 AC XY: 56067 AN XY: 74418

Gnomad4 AFR AF: 0.617

Gnomad4 AMR AF: 0.828

Gnomad4 ASJ AF: 0.765

Gnomad4 EAS AF: 0.966

Gnomad4 SAS AF: 0.887

Gnomad4 FIN AF: 0.755

Gnomad4 NFE AF: 0.781

Gnomad4 OTH AF: 0.761

Alfa AF: 0.767 Hom.: 28216

Bravo AF: 0.750

Asia WGS AF: 0.907 AC: 3152 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	This is a RefSeq error. The reference base (c.1173T) is the minor allele. This a llele (T) has been identified in 21% (1788/8438) of European American chromosome s and 37% (1521/4152) of African American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs760597) and thus meets c riteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Eichsfeld type congenital muscular dystrophy Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	9.2
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs760597; hg19: chr1-26138262; COSMIC: COSV62525913; COSMIC: COSV62525913;