rs187960531

Variant names:

• chr1-25800272-C-T
• rs187960531
• NM_020451.3:c.42C>T

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.42C>T​(p.Pro14Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00465 in 971,178 control chromosomes in the GnomAD database, including 160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (105 hom., cov: 30)
  • Exomes 𝑓: 0.0017 (55 hom.)
• Consequence: SELENON NM_020451.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.588
• Publications: 1 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=-0.51).
• BP6: Variant 1-25800272-C-T is Benign according to our data. Variant chr1-25800272-C-T is described in ClinVar as Benign. ClinVar VariationId is 95964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.588 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0698 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.42C>T	p.Pro14Pro	synonymous	Exon 1 of 13	NP_065184.2
	SELENON	NM_206926.2		c.42C>T	p.Pro14Pro	synonymous	Exon 1 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.42C>T	p.Pro14Pro	synonymous	Exon 1 of 13	ENSP00000355141.2	Q9NZV5-1
	SELENON	ENST00000374315.1	TSL:5	c.42C>T	p.Pro14Pro	synonymous	Exon 1 of 12	ENSP00000363434.1	Q9NZV5-2
	SELENON	ENST00000354177.9	TSL:5	c.42C>T	p.Pro14Pro	synonymous	Exon 1 of 12	ENSP00000346109.5	H9KV50

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3095 AN: 146024 Hom.: 106 Cov.: 30

Gnomad AFR AF: 0.0720

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00324

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00974

Gnomad NFE AF: 0.000274

Gnomad OTH AF: 0.0114

GnomAD2 exomes AF: 0.00433 AC: 11 AN: 2542 AF XY: 0.00633

Gnomad AFR exome AF: 0.0652

Gnomad AMR exome AF: 0.00654

Gnomad ASJ exome AF: 0.00365

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00171 AC: 1413 AN: 825096 Hom.: 55 Cov.: 16 AF XY: 0.00170 AC XY: 650 AN XY: 382938

African (AFR) AF: 0.0753 AC: 1177 AN: 15626

American (AMR) AF: 0.00296 AC: 5 AN: 1690

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 9 AN: 5360

East Asian (EAS) AF: 0.00 AC: 0 AN: 3756

South Asian (SAS) AF: 0.000114 AC: 2 AN: 17586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 466

Middle Eastern (MID) AF: 0.00431 AC: 7 AN: 1624

European-Non Finnish (NFE) AF: 0.000154 AC: 116 AN: 751968

Other (OTH) AF: 0.00359 AC: 97 AN: 27020

GnomAD4 genome AF: 0.0212 AC: 3100 AN: 146082 Hom.: 105 Cov.: 30 AF XY: 0.0201 AC XY: 1431 AN XY: 71066

African (AFR) AF: 0.0720 AC: 2938 AN: 40828

American (AMR) AF: 0.00727 AC: 107 AN: 14726

Ashkenazi Jewish (ASJ) AF: 0.00324 AC: 11 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8248

Middle Eastern (MID) AF: 0.0105 AC: 3 AN: 286

European-Non Finnish (NFE) AF: 0.000274 AC: 18 AN: 65770

Other (OTH) AF: 0.0113 AC: 23 AN: 2034

Alfa AF: 0.0160 Hom.: 10

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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	-0.51
CADD	Benign	13
DANN	Uncertain	0.98
PhyloP100		0.59
PromoterAI		0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs187960531; hg19: chr1-26126763;