rs398124359

Positions:

• chr1-25800333-G-C

Variant summary

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

The NM_020451.3(SELENON):​c.103G>C​(p.Gly35Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,012,816 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 1.37

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=0.36189088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3	c.103G>C	p.Gly35Arg	missense_variant	1/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.103G>C	p.Gly35Arg	missense_variant	1/12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.103G>C	p.Gly35Arg	missense_variant	1/13	1	NM_020451.3	ENSP00000355141
SELENON	ENST00000374315.1	c.103G>C	p.Gly35Arg	missense_variant	1/12	5		ENSP00000363434	P1
SELENON	ENST00000354177.9	c.103G>C	p.Gly35Arg	missense_variant	1/12	5		ENSP00000346109
SELENON	ENST00000494537.2	c.103G>C	p.Gly35Arg	missense_variant, NMD_transcript_variant	1/13	3		ENSP00000508308

Frequencies

GnomAD3 genomes AF: 0.000232 AC: 34 AN: 146850 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000946

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.000121

Gnomad OTH AF: 0.00345

GnomAD4 exome AF: 0.000134 AC: 116 AN: 865896 Hom.: 1 Cov.: 30 AF XY: 0.000129 AC XY: 52 AN XY: 404578

Gnomad4 AFR exome AF: 0.000306

Gnomad4 AMR exome AF: 0.000617

Gnomad4 ASJ exome AF: 0.000161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000587

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.000173

GnomAD4 genome AF: 0.000225 AC: 33 AN: 146920 Hom.: 0 Cov.: 30 AF XY: 0.000280 AC XY: 20 AN XY: 71444

Gnomad4 AFR AF: 0.0000244

Gnomad4 AMR AF: 0.000945

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000121

Gnomad4 OTH AF: 0.00342

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000253

ExAC AF: 0.000161 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	SELENON: PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2017	A variant of uncertain significance has been identified in the SEPN1 gene. The G35R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. No data are available from control populations to assess the frequency of this variant. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 18, 2013	- -

Eichsfeld type congenital muscular dystrophy Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 16, 2023

Variant summary: SELENON c.103G>C (p.Gly35Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 4190 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.103G>C in individuals affected with Eichsfeld Type Congenital Muscular Dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=7) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.103G>C (p.G35R) alteration is located in exon 1 (coding exon 1) of the SEPN1 gene. This alteration results from a G to C substitution at nucleotide position 103, causing the glycine (G) at amino acid position 35 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myopathy with fiber type disproportion Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 13, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

SEPN1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.089	.;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.39	T;T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.69	.;N;N
MutationTaster	Benign	0.85	N;N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.91	N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.097	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.35
MutPred		0.43		Gain of methylation at G35 (P = 0.0158);Gain of methylation at G35 (P = 0.0158);Gain of methylation at G35 (P = 0.0158);
MVP		0.91
MPC		0.28
ClinPred		0.33	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.071

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: rs398124359; hg19: chr1-26126824;