rs982364753

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020451.3(SELENON):​c.4G>A​(p.Gly2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000003 in 666,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3626076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3	c.4G>A	p.Gly2Ser	missense_variant	Exon 1 of 13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.4G>A	p.Gly2Ser	missense_variant	Exon 1 of 12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.4G>A	p.Gly2Ser	missense_variant	Exon 1 of 13	1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1	c.4G>A	p.Gly2Ser	missense_variant	Exon 1 of 12	5		ENSP00000363434.1
SELENON	ENST00000354177.9	c.4G>A	p.Gly2Ser	missense_variant	Exon 1 of 12	5		ENSP00000346109.5
SELENON	ENST00000494537.2	n.4G>A		non_coding_transcript_exon_variant	Exon 1 of 13	3		ENSP00000508308.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000300 AC: 2 AN: 666228 Hom.: 0 Cov.: 8 AF XY: 0.00000645 AC XY: 2 AN XY: 309948

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: 0.00000328 AC: 2 AN: 608862

Other (OTH) AF: 0.00 AC: 0 AN: 21768

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	.;T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.37	T;T;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.69	.;N;N
PhyloP100		-0.22
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.070	N;N;N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.60	T;T;T
Polyphen		0.84, 0.90	.;P;P
Vest4		0.10
MutPred		0.26		Gain of phosphorylation at G2 (P = 5e-04);Gain of phosphorylation at G2 (P = 5e-04);Gain of phosphorylation at G2 (P = 5e-04);
MVP		0.91
MPC		0.23
ClinPred		0.34	T
GERP RS		2.0
PromoterAI		0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
Mutation Taster		=86/14	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;