rs1019702401

Positions:

• chr1-25801116-A-G
• chr1-25801116-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020451.3(SELENON):​c.257A>G​(p.Tyr86Cys) 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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.43

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=0.33885264).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3	c.257A>G	p.Tyr86Cys	missense_variant	2/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.257A>G	p.Tyr86Cys	missense_variant	2/12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.257A>G	p.Tyr86Cys	missense_variant	2/13	1	NM_020451.3	ENSP00000355141
SELENON	ENST00000374315.1	c.257A>G	p.Tyr86Cys	missense_variant	2/12	5		ENSP00000363434	P1
SELENON	ENST00000354177.9	c.257A>G	p.Tyr86Cys	missense_variant	2/12	5		ENSP00000346109
SELENON	ENST00000494537.2	c.257A>G	p.Tyr86Cys	missense_variant, NMD_transcript_variant	2/13	3		ENSP00000508308

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;.
Eigen	Benign	0.087
Eigen_PC	Benign	0.032
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	2.0	.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.036	D;D;D
Polyphen		0.97	.;D;D
Vest4		0.40
MutPred		0.46		Loss of phosphorylation at Y86 (P = 0.0122);Loss of phosphorylation at Y86 (P = 0.0122);Loss of phosphorylation at Y86 (P = 0.0122);
MVP		0.86
MPC		0.75
ClinPred		0.96	D
GERP RS		-0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29

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: rs1019702401; hg19: chr1-26127607;