1-25811710-G-C

Position:

• chr1-25811710-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020451.3(SELENON):​c.1112G>C​(p.Gly371Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G371D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.97

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3	c.1112G>C	p.Gly371Ala	missense_variant	9/13	ENST00000361547.7
SELENON	NM_206926.2	c.1010G>C	p.Gly337Ala	missense_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7	c.1112G>C	p.Gly371Ala	missense_variant	9/13	1	NM_020451.3
SELENON	ENST00000374315.1	c.1010G>C	p.Gly337Ala	missense_variant	8/12	5		P1
SELENON	ENST00000354177.9	c.941G>C	p.Gly314Ala	missense_variant	8/12	5
SELENON	ENST00000494537.2	c.1010G>C	p.Gly337Ala	missense_variant, NMD_transcript_variant	8/13	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000428 AC: 1 AN: 233754 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 127328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000948

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Uncertain	0.54	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.9	D;N;D
REVEL	Pathogenic	0.65
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		1.0, 1.0	.;D;D
Vest4		0.76
MutPred		0.35		.;Loss of catalytic residue at G371 (P = 0.0645);.;
MVP		0.95
MPC		0.39
ClinPred		0.70	D
GERP RS		5.2
Varity_R		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs745886248; hg19: chr1-26138201;