rs115488291

Variant names:

• chr1-25808986-G-A
• rs115488291
• NM_020451.3:c.748-40G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020451.3(SELENON):​c.748-40G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,612,904 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (48 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (50 hom.)
• Consequence: SELENON NM_020451.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.16
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-25808986-G-A is Benign according to our data. Variant chr1-25808986-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 261287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2022/152282) while in subpopulation AFR AF = 0.0457 (1899/41564). AF 95% confidence interval is 0.044. There are 48 homozygotes in GnomAd4. There are 934 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 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.748-40G>A		intron	N/A	NP_065184.2
	SELENON	NM_206926.2		c.646-40G>A		intron	N/A	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.748-40G>A		intron	N/A	ENSP00000355141.2	Q9NZV5-1
	SELENON	ENST00000374315.1	TSL:5	c.646-40G>A		intron	N/A	ENSP00000363434.1	Q9NZV5-2
	SELENON	ENST00000354177.9	TSL:5	c.646-109G>A		intron	N/A	ENSP00000346109.5	H9KV50

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2014 AN: 152164 Hom.: 48 Cov.: 33

Gnomad AFR AF: 0.0457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00334 AC: 825 AN: 247056 AF XY: 0.00251

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.00244

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00141 AC: 2053 AN: 1460622 Hom.: 50 Cov.: 33 AF XY: 0.00127 AC XY: 923 AN XY: 726656

African (AFR) AF: 0.0467 AC: 1562 AN: 33470

American (AMR) AF: 0.00250 AC: 112 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52388

Middle Eastern (MID) AF: 0.00244 AC: 14 AN: 5738

European-Non Finnish (NFE) AF: 0.000145 AC: 161 AN: 1111898

Other (OTH) AF: 0.00321 AC: 194 AN: 60376

GnomAD4 genome AF: 0.0133 AC: 2022 AN: 152282 Hom.: 48 Cov.: 33 AF XY: 0.0125 AC XY: 934 AN XY: 74450

African (AFR) AF: 0.0457 AC: 1899 AN: 41564

American (AMR) AF: 0.00509 AC: 78 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68000

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00734 Hom.: 3

Bravo AF: 0.0150

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.049
DANN	Benign	0.75
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs115488291; hg19: chr1-26135477;