1-25814082-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020451.3(SELENON):​c.1506C>G​(p.Asn502Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. 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: not found (cov: 32)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 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

ENSG00000255054 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3249752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3	c.1506C>G	p.Asn502Lys	missense_variant	Exon 12 of 13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.1404C>G	p.Asn468Lys	missense_variant	Exon 11 of 12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.1506C>G	p.Asn502Lys	missense_variant	Exon 12 of 13	1	NM_020451.3	ENSP00000355141.2
ENSG00000255054	ENST00000527604.1	n.27C>G		non_coding_transcript_exon_variant	Exon 2 of 4	5		ENSP00000457066.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	.;T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.59	T;T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.5	.;L;.
PhyloP100		0.14
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.087
Sift	Benign	0.11	T;T;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.0	.;B;B
Vest4		0.028
MutPred		0.25		.;Gain of ubiquitination at N502 (P = 0.0025);.;
MVP		0.85
MPC		0.27
ClinPred		0.29	T
GERP RS		2.6
Varity_R		0.083
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2294228; hg19: chr1-26140573;