rs147587542

Variant names:

• chr1-25809791-C-T
• rs147587542
• NM_020451.3:c.981C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-25809791-C-T
• chr1-25809791-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020451.3(SELENON):​c.981C>T​(p.Arg327Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 1,613,980 control chromosomes in the GnomAD database, including 1,486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (73 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1413 hom.)
• Consequence: SELENON NM_020451.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.77
• Publications: 4 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, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics
• 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-25809791-C-T is Benign according to our data. Variant chr1-25809791-C-T is described in ClinVar as Benign. ClinVar VariationId is 95967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0269 (4095/152320) while in subpopulation NFE AF = 0.0434 (2949/68018). AF 95% confidence interval is 0.0421. There are 73 homozygotes in GnomAd4. There are 1877 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 73 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020451.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	NM_020451.3	MANE Select	c.981C>T	p.Arg327Arg	synonymous	Exon 7 of 13	NP_065184.2
	SELENON	NM_206926.2		c.879C>T	p.Arg293Arg	synonymous	Exon 6 of 12	NP_996809.1	Q9NZV5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	ENST00000361547.7	TSL:1 MANE Select	c.981C>T	p.Arg327Arg	synonymous	Exon 7 of 13	ENSP00000355141.2	Q9NZV5-1
	SELENON	ENST00000374315.1	TSL:5	c.879C>T	p.Arg293Arg	synonymous	Exon 6 of 12	ENSP00000363434.1	Q9NZV5-2
	SELENON	ENST00000354177.9	TSL:5	c.810C>T	p.Arg270Arg	synonymous	Exon 6 of 12	ENSP00000346109.5	H9KV50

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4096 AN: 152202 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.00844

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0256 AC: 6380 AN: 249420 AF XY: 0.0250

Gnomad AFR exome AF: 0.00735

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.0217

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.0411

Gnomad OTH exome AF: 0.0292

GnomAD4 exome AF: 0.0393 AC: 57506 AN: 1461660 Hom.: 1413 Cov.: 32 AF XY: 0.0384 AC XY: 27902 AN XY: 727134

African (AFR) AF: 0.00600 AC: 201 AN: 33480

American (AMR) AF: 0.0195 AC: 872 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 665 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00649 AC: 560 AN: 86258

European-Finnish (FIN) AF: 0.0181 AC: 964 AN: 53220

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.0470 AC: 52225 AN: 1111982

Other (OTH) AF: 0.0328 AC: 1983 AN: 60392

GnomAD4 genome AF: 0.0269 AC: 4095 AN: 152320 Hom.: 73 Cov.: 32 AF XY: 0.0252 AC XY: 1877 AN XY: 74474

African (AFR) AF: 0.00842 AC: 350 AN: 41576

American (AMR) AF: 0.0245 AC: 375 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4824

European-Finnish (FIN) AF: 0.0187 AC: 198 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0434 AC: 2949 AN: 68018

Other (OTH) AF: 0.0303 AC: 64 AN: 2114

Alfa AF: 0.0364 Hom.: 73

Bravo AF: 0.0268

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0376

EpiControl AF: 0.0376

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	1	Eichsfeld type congenital muscular dystrophy (1)
-	-	1	SEPN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.18
DANN	Benign	0.90
PhyloP100		-2.8
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: rs147587542; hg19: chr1-26136282; COSMIC: COSV62524818; COSMIC: COSV62524818;