rs10902685

chr1-25812646-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020451.3(SELENON):c.1282-41C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.774 in 1,525,118 control chromosomes in the GnomAD database, including 467,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (36519 hom., cov: 25)
  • Exomes 𝑓: 0.79 (430938 hom.)
• Consequence: SELENON NM_020451.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0280

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 (BayesDel_noAF=-0.84).
• BP6: Variant 1-25812646-C-T is Benign according to our data. Variant chr1-25812646-C-T is described in ClinVar as [Benign]. Clinvar id is 261274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25812646-C-T is described in Lovd as [Benign].
• 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.1282-41C>T		intron_variant		ENST00000361547.7
SELENON	NM_206926.2	c.1180-41C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7	c.1282-41C>T		intron_variant		1	NM_020451.3
SELENON	ENST00000354177.9	c.1111-41C>T		intron_variant		5
SELENON	ENST00000374315.1	c.1180-41C>T		intron_variant		5		P1
SELENON	ENST00000494537.2	c.1180-41C>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.658 AC: 98897 AN: 150196 Hom.: 36507 Cov.: 25

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.938

Gnomad AMR AF: 0.793

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.966

Gnomad SAS AF: 0.886

Gnomad FIN AF: 0.753

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.780

Gnomad OTH AF: 0.702

GnomAD3 exomes AF: 0.793 AC: 166235 AN: 209640 Hom.: 67996 AF XY: 0.800 AC XY: 91013 AN XY: 113744

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.879

Gnomad ASJ exome AF: 0.773

Gnomad EAS exome AF: 0.966

Gnomad SAS exome AF: 0.878

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.787

Gnomad OTH exome AF: 0.800

GnomAD4 exome AF: 0.786 AC: 1080867 AN: 1374802 Hom.: 430938 Cov.: 20 AF XY: 0.790 AC XY: 541910 AN XY: 685702

Gnomad4 AFR exome AF: 0.284

Gnomad4 AMR exome AF: 0.869

Gnomad4 ASJ exome AF: 0.770

Gnomad4 EAS exome AF: 0.961

Gnomad4 SAS exome AF: 0.879

Gnomad4 FIN exome AF: 0.745

Gnomad4 NFE exome AF: 0.787

Gnomad4 OTH exome AF: 0.774

GnomAD4 genome AF: 0.658 AC: 98932 AN: 150316 Hom.: 36519 Cov.: 25 AF XY: 0.664 AC XY: 48651 AN XY: 73240

Gnomad4 AFR AF: 0.300

Gnomad4 AMR AF: 0.793

Gnomad4 ASJ AF: 0.766

Gnomad4 EAS AF: 0.967

Gnomad4 SAS AF: 0.885

Gnomad4 FIN AF: 0.753

Gnomad4 NFE AF: 0.780

Gnomad4 OTH AF: 0.704

Alfa AF: 0.725 Hom.: 7763

Bravo AF: 0.647

Asia WGS AF: 0.883 AC: 3067 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Eichsfeld type congenital muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.2
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.98

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: rs10902685; hg19: chr1-26139137;