rs115852080

Variant names:

• chr1-25808625-G-A
• rs115852080
• NM_020451.3:c.583G>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.583G>A​(p.Ala195Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,613,668 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 33)
  • Exomes 𝑓: 0.013 (166 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.25
• Publications: 10 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004422933).
• BP6: Variant 1-25808625-G-A is Benign according to our data. Variant chr1-25808625-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0106 (1611/152086) while in subpopulation NFE AF = 0.015 (1017/67920). AF 95% confidence interval is 0.0142. There are 28 homozygotes in GnomAd4. There are 711 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	NM_020451.3	MANE Select	c.583G>A	p.Ala195Thr	missense	Exon 5 of 13	NP_065184.2
	SELENON	NM_206926.2		c.481G>A	p.Ala161Thr	missense	Exon 4 of 12	NP_996809.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	ENST00000361547.7	TSL:1 MANE Select	c.583G>A	p.Ala195Thr	missense	Exon 5 of 13	ENSP00000355141.2
	SELENON	ENST00000374315.1	TSL:5	c.481G>A	p.Ala161Thr	missense	Exon 4 of 12	ENSP00000363434.1
	SELENON	ENST00000354177.9	TSL:5	c.481G>A	p.Ala161Thr	missense	Exon 4 of 12	ENSP00000346109.5

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1610 AN: 151968 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.00464

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0101 AC: 2498 AN: 248090 AF XY: 0.0106

Gnomad AFR exome AF: 0.00498

Gnomad AMR exome AF: 0.00742

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00266

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0141

GnomAD4 exome AF: 0.0133 AC: 19496 AN: 1461582 Hom.: 166 Cov.: 32 AF XY: 0.0134 AC XY: 9765 AN XY: 727110

African (AFR) AF: 0.00523 AC: 175 AN: 33478

American (AMR) AF: 0.00787 AC: 352 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 281 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00920 AC: 794 AN: 86258

European-Finnish (FIN) AF: 0.00250 AC: 133 AN: 53178

Middle Eastern (MID) AF: 0.0150 AC: 86 AN: 5752

European-Non Finnish (NFE) AF: 0.0152 AC: 16883 AN: 1111972

Other (OTH) AF: 0.0131 AC: 789 AN: 60392

GnomAD4 genome AF: 0.0106 AC: 1611 AN: 152086 Hom.: 28 Cov.: 33 AF XY: 0.00956 AC XY: 711 AN XY: 74348

African (AFR) AF: 0.00465 AC: 193 AN: 41488

American (AMR) AF: 0.00883 AC: 135 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4824

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10604

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0150 AC: 1017 AN: 67920

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.0133 Hom.: 26

Bravo AF: 0.0114

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00510 AC: 21

ESP6500EA AF: 0.0155 AC: 130

ExAC AF: 0.00999 AC: 1208

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0176

EpiControl AF: 0.0165

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	Eichsfeld type congenital muscular dystrophy (1)
-	-	1	SEPN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.044
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0044	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.40
Sift	Benign	0.059	T
Sift4G	Benign	0.44	T
Polyphen		0.95	P
Vest4		0.34
MVP		0.92
MPC		0.28
ClinPred		0.015	T
GERP RS		4.0
Varity_R		0.056
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs115852080; hg19: chr1-26135116; COSMIC: COSV99052738; COSMIC: COSV99052738;