1-25800232-T-A

Position:

• chr1-25800232-T-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_020451.3(SELENON):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000695 in 143,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000070 (0 hom., cov: 30)
• Consequence: SELENON NM_020451.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.62

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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_020451.3 (SELENON) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-25800232-T-A is Pathogenic according to our data. Variant chr1-25800232-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1701096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3	c.2T>A	p.Met1?	start_lost	1/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.2T>A	p.Met1?	start_lost	1/12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.2T>A	p.Met1?	start_lost	1/13	1	NM_020451.3	ENSP00000355141
SELENON	ENST00000374315.1	c.2T>A	p.Met1?	start_lost	1/12	5		ENSP00000363434	P1
SELENON	ENST00000354177.9	c.2T>A	p.Met1?	start_lost	1/12	5		ENSP00000346109
SELENON	ENST00000494537.2	c.2T>A	p.Met1?	start_lost, NMD_transcript_variant	1/13	3		ENSP00000508308

Frequencies

GnomAD3 genomes AF: 0.00000695 AC: 1 AN: 143788 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000154

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 8

GnomAD4 genome AF: 0.00000695 AC: 1 AN: 143788 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 69862

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000154

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Breakthrough Genomics, Breakthrough Genomics

Apr 30, 2021

This variant has not been previously reported in population or public databases or in the literature. However, two other substitution variants affecting this residue such as; c.2T>C; p.M1T and c.2T>G ;M1R has been previously reported as ‘pathogenic’ in the context of Eichsfeld type congenital muscular dystrophy. In addition, variants disrupting the initiator codon such as; p.Met1Val and c.2dup (represented as 1_2insT in the article) have been previously observed in multiple unrelated individuals of various ethnic origins affected with SELENON-related congenital myopathies and muscular dystrophy [PMID: 1219264, 23394784, 16779558] -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.092	.;T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.030	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	-0.041	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-0.43	N;N;N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.46, 0.60	.;P;P
Vest4		0.27
MutPred		0.99		Loss of stability (P = 0.0274);Loss of stability (P = 0.0274);Loss of stability (P = 0.0274);
MVP		0.91
ClinPred		0.97	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92

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: rs1174570887; hg19: chr1-26126723;