1-25808728-G-C

Position:

• chr1-25808728-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020451.3(SELENON):​c.686G>C​(p.Ser229Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,768 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2299029).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3	c.686G>C	p.Ser229Thr	missense_variant	5/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.584G>C	p.Ser195Thr	missense_variant	4/12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.686G>C	p.Ser229Thr	missense_variant	5/13	1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1	c.584G>C	p.Ser195Thr	missense_variant	4/12	5		ENSP00000363434.1
SELENON	ENST00000354177.9	c.584G>C	p.Ser195Thr	missense_variant	4/12	5		ENSP00000346109.5
SELENON	ENST00000494537.2	n.584G>C		non_coding_transcript_exon_variant	4/13	3		ENSP00000508308.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461768 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	0.0097	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Benign	0.61
DEOGEN2	Benign	0.084	.;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.84	.;L;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.27	N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.84	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.17, 0.11	.;B;B
Vest4		0.53
MutPred		0.22		.;Gain of helix (P = 0.0696);.;
MVP		0.89
MPC		0.23
ClinPred		0.52	D
GERP RS		4.9
Varity_R		0.076

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56169842; hg19: chr1-26135219;