rs10902685

Variant names:

• chr1-25812646-C-T
• rs10902685
• NM_020451.3:c.1282-41C>T

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: -0.0280
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• rigid spine muscular dystrophy 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, G2P
• SELENON-related myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital myopathy 4A, autosomal dominant

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• desmin-related myopathy with Mallory body-like inclusions

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• rigid spine syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255054 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SELENON	NM_020451.3	c.1282-41C>T		intron_variant	Intron 9 of 12	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.1180-41C>T		intron_variant	Intron 8 of 11		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.1282-41C>T		intron_variant	Intron 9 of 12	1	NM_020451.3	ENSP00000355141.2

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

GnomAD2 exomes AF: 0.793 AC: 166235 AN: 209640 AF XY: 0.800

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 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

African (AFR) AF: 0.284 AC: 8982 AN: 31632

American (AMR) AF: 0.869 AC: 36231 AN: 41684

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 19472 AN: 25288

East Asian (EAS) AF: 0.961 AC: 36598 AN: 38092

South Asian (SAS) AF: 0.879 AC: 71271 AN: 81106

European-Finnish (FIN) AF: 0.745 AC: 36872 AN: 49502

Middle Eastern (MID) AF: 0.815 AC: 3301 AN: 4052

European-Non Finnish (NFE) AF: 0.787 AC: 823781 AN: 1046122

Other (OTH) AF: 0.774 AC: 44359 AN: 57324

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

African (AFR) AF: 0.300 AC: 12237 AN: 40852

American (AMR) AF: 0.793 AC: 11980 AN: 15106

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 2649 AN: 3460

East Asian (EAS) AF: 0.967 AC: 4905 AN: 5074

South Asian (SAS) AF: 0.885 AC: 4107 AN: 4642

European-Finnish (FIN) AF: 0.753 AC: 7751 AN: 10288

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.780 AC: 52731 AN: 67606

Other (OTH) AF: 0.704 AC: 1469 AN: 2086

Alfa AF: 0.725 Hom.: 13525

Bravo AF: 0.647

Asia WGS AF: 0.883 AC: 3067 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Eichsfeld type congenital muscular dystrophy Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.66
PhyloP100		-0.028
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.98
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10902685; hg19: chr1-26139137;