1-25814082-C-G

Position:

• chr1-25814082-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/19 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 same amino acid change has been previously reported as Benignin Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.140

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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/exons	MANE	Protein	UniProt
SELENON	NM_020451.3	c.1506C>G	p.Asn502Lys	missense_variant	12/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.1404C>G	p.Asn468Lys	missense_variant	11/12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.1506C>G	p.Asn502Lys	missense_variant	12/13	1	NM_020451.3	ENSP00000355141
SELENON	ENST00000374315.1	c.1404C>G	p.Asn468Lys	missense_variant	11/12	5		ENSP00000363434	P1
SELENON	ENST00000354177.9	c.1335C>G	p.Asn445Lys	missense_variant	11/12	5		ENSP00000346109
SELENON	ENST00000494537.2	c.*26C>G		3_prime_UTR_variant, NMD_transcript_variant	12/13	3		ENSP00000508308

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
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;.
MutationTaster	Benign	1.0	P;P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2294228; hg19: chr1-26140573;