NM_020451.3:c.1173T>C

Variant names:

• chr1-25811771-T-C
• rs760597
• NM_020451.3:c.1173T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020451.3(SELENON):​c.1173T>C​(p.Pro391Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.79 in 1,592,998 control chromosomes in the GnomAD database, including 499,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43500 hom., cov: 34)
  • Exomes 𝑓: 0.79 (456466 hom.)
• Consequence: SELENON NM_020451.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.302
• Publications: 25 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

ENSG00000255054 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-25811771-T-C is Benign according to our data. Variant chr1-25811771-T-C is described in ClinVar as Benign. ClinVar VariationId is 95956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.302 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

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.1173T>C	p.Pro391Pro	synonymous	Exon 9 of 13	NP_065184.2
	SELENON	NM_206926.2		c.1071T>C	p.Pro357Pro	synonymous	Exon 8 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.1173T>C	p.Pro391Pro	synonymous	Exon 9 of 13	ENSP00000355141.2	Q9NZV5-1
	SELENON	ENST00000374315.1	TSL:5	c.1071T>C	p.Pro357Pro	synonymous	Exon 8 of 12	ENSP00000363434.1	Q9NZV5-2
	SELENON	ENST00000354177.9	TSL:5	c.1002T>C	p.Pro334Pro	synonymous	Exon 8 of 12	ENSP00000346109.5	H9KV50

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113974 AN: 152086 Hom.: 43465 Cov.: 34

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.939

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.966

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.759

GnomAD2 exomes AF: 0.810 AC: 171867 AN: 212212 AF XY: 0.812

Gnomad AFR exome AF: 0.607

Gnomad AMR exome AF: 0.891

Gnomad ASJ exome AF: 0.771

Gnomad EAS exome AF: 0.965

Gnomad FIN exome AF: 0.741

Gnomad NFE exome AF: 0.784

Gnomad OTH exome AF: 0.811

GnomAD4 exome AF: 0.794 AC: 1144177 AN: 1440794 Hom.: 456466 Cov.: 61 AF XY: 0.797 AC XY: 569704 AN XY: 714946

African (AFR) AF: 0.606 AC: 20167 AN: 33266

American (AMR) AF: 0.884 AC: 35508 AN: 40168

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 19746 AN: 25656

East Asian (EAS) AF: 0.960 AC: 37432 AN: 38976

South Asian (SAS) AF: 0.878 AC: 73352 AN: 83514

European-Finnish (FIN) AF: 0.744 AC: 38639 AN: 51952

Middle Eastern (MID) AF: 0.822 AC: 4707 AN: 5728

European-Non Finnish (NFE) AF: 0.787 AC: 867235 AN: 1101882

Other (OTH) AF: 0.794 AC: 47391 AN: 59652

GnomAD4 genome AF: 0.749 AC: 114063 AN: 152204 Hom.: 43500 Cov.: 34 AF XY: 0.753 AC XY: 56067 AN XY: 74418

African (AFR) AF: 0.617 AC: 25614 AN: 41520

American (AMR) AF: 0.828 AC: 12677 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 2656 AN: 3470

East Asian (EAS) AF: 0.966 AC: 4996 AN: 5170

South Asian (SAS) AF: 0.887 AC: 4284 AN: 4828

European-Finnish (FIN) AF: 0.755 AC: 7999 AN: 10598

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.781 AC: 53115 AN: 67990

Other (OTH) AF: 0.761 AC: 1609 AN: 2114

Alfa AF: 0.766 Hom.: 31555

Bravo AF: 0.750

Asia WGS AF: 0.907 AC: 3152 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	Eichsfeld type congenital muscular dystrophy (3)
-	-	2	not provided (2)
-	-	1	SEPN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.2
DANN	Benign	0.84
PhyloP100		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs760597; hg19: chr1-26138262; COSMIC: COSV62525913; COSMIC: COSV62525913;