rs982364753

Positions:

• chr1-25800234-G-T

Variant summary

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

The ENST00000361547.7(SELENON):​c.4G>T​(p.Gly2Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 812,036 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00025 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: SELENON ENST00000361547.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.219

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=0.406279).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3	c.4G>T	p.Gly2Cys	missense_variant	1/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.4G>T	p.Gly2Cys	missense_variant	1/12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.4G>T	p.Gly2Cys	missense_variant	1/13	1	NM_020451.3	ENSP00000355141
SELENON	ENST00000374315.1	c.4G>T	p.Gly2Cys	missense_variant	1/12	5		ENSP00000363434	P1
SELENON	ENST00000354177.9	c.4G>T	p.Gly2Cys	missense_variant	1/12	5		ENSP00000346109
SELENON	ENST00000494537.2	c.4G>T	p.Gly2Cys	missense_variant, NMD_transcript_variant	1/13	3		ENSP00000508308

Frequencies

GnomAD3 genomes AF: 0.000247 AC: 36 AN: 145810 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000737

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000487

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000374 AC: 249 AN: 666226 Hom.: 0 Cov.: 8 AF XY: 0.000361 AC XY: 112 AN XY: 309946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000401

Gnomad4 OTH exome AF: 0.000230

GnomAD4 genome AF: 0.000247 AC: 36 AN: 145810 Hom.: 0 Cov.: 30 AF XY: 0.000212 AC XY: 15 AN XY: 70896

Gnomad4 AFR AF: 0.0000737

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000122

Gnomad4 NFE AF: 0.000487

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000268

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

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	Sep 26, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2022	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 2 of the SELENON protein (p.Gly2Cys). This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SELENON-related conditions. ClinVar contains an entry for this variant (Variation ID: 426515). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SELENON protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.4G>T (p.G2C) alteration is located in exon 1 (coding exon 1) of the SEPN1 gene. This alteration results from a G to T substitution at nucleotide position 4, causing the glycine (G) at amino acid position 2 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 01, 2020

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.10	.;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.29	T;T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.69	.;N;N
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.99, 1.0	.;D;D
Vest4		0.11
MutPred		0.30		Gain of catalytic residue at G2 (P = 0.0295);Gain of catalytic residue at G2 (P = 0.0295);Gain of catalytic residue at G2 (P = 0.0295);
MVP		0.89
MPC		0.25
ClinPred		0.42	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27

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: rs982364753; hg19: chr1-26126725;