rs2294228

Variant names:

• chr1-25814082-C-A
• rs2294228
• NM_020451.3:c.1506C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-25814082-C-A
• chr1-25814082-C-G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020451.3(SELENON):​c.1506C>A​(p.Asn502Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 1,613,192 control chromosomes in the GnomAD database, including 493,293 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N502Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.66 (36901 hom., cov: 32)
  • Exomes 𝑓: 0.79 (456392 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.140
• Publications: 46 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 -16 ACMG points.

• BP6: Variant 1-25814082-C-A is Benign according to our data. Variant chr1-25814082-C-A is described in ClinVar as Benign. ClinVar VariationId is 95959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.1506C>A	p.Asn502Lys	missense	Exon 12 of 13	NP_065184.2
	SELENON	NM_206926.2		c.1404C>A	p.Asn468Lys	missense	Exon 11 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.1506C>A	p.Asn502Lys	missense	Exon 12 of 13	ENSP00000355141.2	Q9NZV5-1
	ENSG00000255054	ENST00000527604.1	TSL:5	n.27C>A		non_coding_transcript_exon	Exon 2 of 4	ENSP00000457066.1	H3BT81
	SELENON	ENST00000374315.1	TSL:5	c.1404C>A	p.Asn468Lys	missense	Exon 11 of 12	ENSP00000363434.1	Q9NZV5-2

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100083 AN: 151980 Hom.: 36889 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.939

Gnomad AMR AF: 0.792

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.966

Gnomad SAS AF: 0.887

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.780

Gnomad OTH AF: 0.701

GnomAD2 exomes AF: 0.786 AC: 196103 AN: 249356 AF XY: 0.794

Gnomad AFR exome AF: 0.291

Gnomad AMR exome AF: 0.879

Gnomad ASJ exome AF: 0.771

Gnomad EAS exome AF: 0.965

Gnomad FIN exome AF: 0.743

Gnomad NFE exome AF: 0.782

Gnomad OTH exome AF: 0.795

GnomAD4 exome AF: 0.785 AC: 1147072 AN: 1461094 Hom.: 456392 Cov.: 44 AF XY: 0.789 AC XY: 573642 AN XY: 726922

African (AFR) AF: 0.284 AC: 9497 AN: 33462

American (AMR) AF: 0.870 AC: 38912 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 20089 AN: 26130

East Asian (EAS) AF: 0.961 AC: 38131 AN: 39696

South Asian (SAS) AF: 0.878 AC: 75691 AN: 86250

European-Finnish (FIN) AF: 0.744 AC: 39742 AN: 53400

Middle Eastern (MID) AF: 0.803 AC: 4634 AN: 5768

European-Non Finnish (NFE) AF: 0.786 AC: 873751 AN: 1111294

Other (OTH) AF: 0.772 AC: 46625 AN: 60370

GnomAD4 genome AF: 0.658 AC: 100115 AN: 152098 Hom.: 36901 Cov.: 32 AF XY: 0.665 AC XY: 49453 AN XY: 74396

African (AFR) AF: 0.301 AC: 12481 AN: 41454

American (AMR) AF: 0.793 AC: 12110 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 2657 AN: 3472

East Asian (EAS) AF: 0.966 AC: 4999 AN: 5174

South Asian (SAS) AF: 0.886 AC: 4282 AN: 4834

European-Finnish (FIN) AF: 0.755 AC: 8003 AN: 10598

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.780 AC: 52989 AN: 67966

Other (OTH) AF: 0.703 AC: 1487 AN: 2114

Alfa AF: 0.751 Hom.: 182828

Bravo AF: 0.646

TwinsUK AF: 0.788 AC: 2923

ALSPAC AF: 0.789 AC: 3041

ESP6500AA AF: 0.324 AC: 1388

ESP6500EA AF: 0.787 AC: 6682

ExAC AF: 0.773 AC: 93611

Asia WGS AF: 0.885 AC: 3076 AN: 3478

EpiCase AF: 0.795

EpiControl AF: 0.799

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Eichsfeld type congenital muscular dystrophy (4)
-	-	2	not provided (2)
-	-	1	SEPN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	8.1e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.14
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.085
Sift	Benign	0.11	T
Sift4G	Uncertain	0.020	D
Polyphen		0.0	B
Vest4		0.028
MutPred		0.25		Gain of ubiquitination at N502 (P = 0.0025)
MPC		0.27
ClinPred		0.012	T
GERP RS		2.6
Varity_R		0.083
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: 22

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2294228; hg19: chr1-26140573; COSMIC: COSV62525671; COSMIC: COSV62525671;