1-25813890-G-A

Variant names:

• chr1-25813890-G-A
• rs121908185
• NM_020451.3:c.1397G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PM5 PP5_Very_Strong

The NM_020451.3(SELENON):​c.1397G>A​(p.Arg466Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000824580: Experimental studies have shown that this missense change affects SELENON function (PMID:18713863, 19067361)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R466W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 7.77
• Publications: 17 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000824580: Experimental studies have shown that this missense change affects SELENON function (PMID: 18713863, 19067361).; SCV003761244: "In vitro functional studies provide some evidence that the p.Arg466Gln variant may impact protein function." PMID:19067361, 18713863; SCV004021168: "At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absence of SELENON protein and functionally diminished capacity of ryanodine binding, which can be rescued by Zebrafish SELENON (Jurynec_2008). Maiti_2009 also suggest this variant weakens the secondary structure of the Selenocysteine Redefinition Element, reduces selenocysteine insertion efficiency and SELENON RNA levels. These data indicate that the variant is very likely to be associated with disease." PMID: 11528383, 33652732, 17951086, 21670436, 18713863, 17951086; SCV000490794: Western blot analysis showed that patients with the R466Q variant and another SELENON variant had significantly decreased levels of selenoprotein N as compared to wild type controls (Maiti et al., 2009);; SCV000915406: Functional testing in muscle cell homogenates from an individual who was homozygous for the p.Arg466Gln variant, showed absence of expression of SEPN1 protein, and significantly reduced ryanodine binding capacity (Jurynec et al. 2008). In addition, Maiti et al. (2009) demonstrated a three-fold reduction in translation of a luciferase reporter construct in 293FT cells carrying the p.Arg466Gln variant compared to wild type.; SCV001365925: in vitro functional studies support an impact of this variant on protein function (Jurynec 2008, Maiti 2009).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_020451.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-25813889-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1415561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 1-25813890-G-A is Pathogenic according to our data. Variant chr1-25813890-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1397G>A	p.Arg466Gln	missense	Exon 11 of 13	NP_065184.2
	SELENON	NM_206926.2		c.1295G>A	p.Arg432Gln	missense	Exon 10 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.1397G>A	p.Arg466Gln	missense	Exon 11 of 13	ENSP00000355141.2	Q9NZV5-1
	SELENON	ENST00000374315.1	TSL:5	c.1295G>A	p.Arg432Gln	missense	Exon 10 of 12	ENSP00000363434.1	Q9NZV5-2
	SELENON	ENST00000354177.9	TSL:5	c.1226G>A	p.Arg409Gln	missense	Exon 10 of 12	ENSP00000346109.5	H9KV50

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000481 AC: 12 AN: 249298 AF XY: 0.0000665

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000120 AC: 175 AN: 1461634 Hom.: 0 Cov.: 31 AF XY: 0.000120 AC XY: 87 AN XY: 727126

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000148 AC: 165 AN: 1111838

Other (OTH) AF: 0.0000497 AC: 3 AN: 60390

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74334

African (AFR) AF: 0.0000483 AC: 2 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.0000579 AC: 7

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Eichsfeld type congenital muscular dystrophy (7)
4	-	-	not provided (4)
1	-	-	Cleft lip/palate (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Muscular dystrophy (1)
1	-	-	SEPN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.73
Sift	Benign	0.069	T
Sift4G	Benign	0.23	T
Polyphen		0.95	P
Vest4		0.97
MVP		0.94
MPC		0.93
ClinPred		0.31	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.22
Mutation Taster		=12/88	disease causing (ClinVar)

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: rs121908185; hg19: chr1-26140381; COSMIC: COSV62524504; COSMIC: COSV62524504;