rs398124359

Variant names:

• chr1-25800333-G-C
• rs398124359
• NM_020451.3:c.103G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

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:8 B:2
• Conservation: PhyloP100: 1.37
• Publications: 0 publications found

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]

SELENON Gene-Disease associations (from GenCC):

• rigid spine muscular dystrophy 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, G2P
• SELENON-related myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital myopathy 4A, autosomal dominant

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• desmin-related myopathy with Mallory body-like inclusions

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• rigid spine syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36189088).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000134 (116/865896) while in subpopulation MID AF = 0.00397 (7/1762). AF 95% confidence interval is 0.00186. There are 1 homozygotes in GnomAdExome4. There are 52 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020451.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	NM_020451.3	MANE Select	c.103G>C	p.Gly35Arg	missense	Exon 1 of 13	NP_065184.2
	SELENON	NM_206926.2		c.103G>C	p.Gly35Arg	missense	Exon 1 of 12	NP_996809.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	ENST00000361547.7	TSL:1 MANE Select	c.103G>C	p.Gly35Arg	missense	Exon 1 of 13	ENSP00000355141.2
	SELENON	ENST00000374315.1	TSL:5	c.103G>C	p.Gly35Arg	missense	Exon 1 of 12	ENSP00000363434.1
	SELENON	ENST00000354177.9	TSL:5	c.103G>C	p.Gly35Arg	missense	Exon 1 of 12	ENSP00000346109.5

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 4190 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.000306 AC: 5 AN: 16340

American (AMR) AF: 0.000617 AC: 2 AN: 3242

Ashkenazi Jewish (ASJ) AF: 0.000161 AC: 1 AN: 6206

East Asian (EAS) AF: 0.00 AC: 0 AN: 4732

South Asian (SAS) AF: 0.000587 AC: 11 AN: 18732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2778

Middle Eastern (MID) AF: 0.00397 AC: 7 AN: 1762

European-Non Finnish (NFE) AF: 0.000109 AC: 85 AN: 783138

Other (OTH) AF: 0.000173 AC: 5 AN: 28966

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

African (AFR) AF: 0.0000244 AC: 1 AN: 40964

American (AMR) AF: 0.000945 AC: 14 AN: 14818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8600

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.000121 AC: 8 AN: 66008

Other (OTH) AF: 0.00342 AC: 7 AN: 2048

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000253

ExAC AF: 0.000161 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	-	2	Eichsfeld type congenital muscular dystrophy (2)
-	1	-	Congenital myopathy with fiber type disproportion (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	1	-	SEPN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
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
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.91	N
REVEL	Uncertain	0.30
Sift	Benign	0.097	T
Sift4G	Benign	0.39	T
Polyphen		1.0	D
Vest4		0.35
MutPred		0.43		Gain of methylation at G35 (P = 0.0158)
MVP		0.91
MPC		0.28
ClinPred		0.33	T
GERP RS		2.1
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.071
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs398124359; hg19: chr1-26126824;