NM_020451.3:c.550G>C

Variant names:

• chr1-25808592-G-C
• rs199742668
• NM_020451.3:c.550G>C

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.550G>C​(p.Ala184Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00049 in 1,613,288 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A184T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 2.49
• 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 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=0.010834575).
• BP6: Variant 1-25808592-G-C is Benign according to our data. Variant chr1-25808592-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 297024.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 = 0.00264 (401/151828) while in subpopulation AFR AF = 0.00904 (374/41394). AF 95% confidence interval is 0.00828. There are 2 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.550G>C	p.Ala184Pro	missense	Exon 5 of 13	NP_065184.2
	SELENON	NM_206926.2		c.448G>C	p.Ala150Pro	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.550G>C	p.Ala184Pro	missense	Exon 5 of 13	ENSP00000355141.2
	SELENON	ENST00000374315.1	TSL:5	c.448G>C	p.Ala150Pro	missense	Exon 4 of 12	ENSP00000363434.1
	SELENON	ENST00000354177.9	TSL:5	c.448G>C	p.Ala150Pro	missense	Exon 4 of 12	ENSP00000346109.5

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 396 AN: 151708 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000694 AC: 172 AN: 247778 AF XY: 0.000468

Gnomad AFR exome AF: 0.00984

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000267 AC: 390 AN: 1461460 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 156 AN XY: 727036

African (AFR) AF: 0.00938 AC: 314 AN: 33472

American (AMR) AF: 0.000447 AC: 20 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53176

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5700

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111934

Other (OTH) AF: 0.000762 AC: 46 AN: 60376

GnomAD4 genome AF: 0.00264 AC: 401 AN: 151828 Hom.: 2 Cov.: 33 AF XY: 0.00249 AC XY: 185 AN XY: 74204

African (AFR) AF: 0.00904 AC: 374 AN: 41394

American (AMR) AF: 0.00157 AC: 24 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67890

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.00308

ESP6500AA AF: 0.00754 AC: 31

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000819 AC: 99

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.092
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.7	L
PhyloP100		2.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.71
Sift	Benign	0.046	D
Sift4G	Benign	0.13	T
Polyphen		0.91	P
Vest4		0.54
MVP		0.94
MPC		0.31
ClinPred		0.036	T
GERP RS		4.5
Varity_R		0.22
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs199742668; hg19: chr1-26135083; COSMIC: COSV108869497; COSMIC: COSV108869497;