rs982364753

Variant names:

• chr1-25800234-G-T
• rs982364753
• NM_020451.3:c.4G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-25800234-G-T
• chr1-25800234-G-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_020451.3(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. 12/21 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 NM_020451.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.219
• 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, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics
• 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.406279).

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.4G>T	p.Gly2Cys	missense	Exon 1 of 13	NP_065184.2
	SELENON	NM_206926.2		c.4G>T	p.Gly2Cys	missense	Exon 1 of 12	NP_996809.1	Q9NZV5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	ENST00000361547.7	TSL:1 MANE Select	c.4G>T	p.Gly2Cys	missense	Exon 1 of 13	ENSP00000355141.2	Q9NZV5-1
	SELENON	ENST00000374315.1	TSL:5	c.4G>T	p.Gly2Cys	missense	Exon 1 of 12	ENSP00000363434.1	Q9NZV5-2
	SELENON	ENST00000354177.9	TSL:5	c.4G>T	p.Gly2Cys	missense	Exon 1 of 12	ENSP00000346109.5	H9KV50

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

African (AFR) AF: 0.00 AC: 0 AN: 12522

American (AMR) AF: 0.00 AC: 0 AN: 778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4132

East Asian (EAS) AF: 0.00 AC: 0 AN: 2856

South Asian (SAS) AF: 0.00 AC: 0 AN: 13774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1314

European-Non Finnish (NFE) AF: 0.000401 AC: 244 AN: 608860

Other (OTH) AF: 0.000230 AC: 5 AN: 21768

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

African (AFR) AF: 0.0000737 AC: 3 AN: 40718

American (AMR) AF: 0.00 AC: 0 AN: 14708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.000122 AC: 1 AN: 8228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.000487 AC: 32 AN: 65660

Other (OTH) AF: 0.00 AC: 0 AN: 2012

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000268

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Eichsfeld type congenital muscular dystrophy (2)
-	1	-	Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
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
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.22
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.12	T
Polyphen		0.99	D
Vest4		0.11
MutPred		0.30		Gain of catalytic residue at G2 (P = 0.0295)
MVP		0.89
MPC		0.25
ClinPred		0.42	T
GERP RS		2.0
PromoterAI		-0.0090	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
Mutation Taster		=85/15	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: rs982364753; hg19: chr1-26126725;