1-25800232-T-G

Variant names:

• chr1-25800232-T-G
• rs1174570887
• NM_020451.3:c.2T>G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_020451.3(SELENON):​c.2T>G​(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 0.00000159 in 628,544 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: not found (cov: 30)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: SELENON NM_020451.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.62
• 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: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 27 pathogenic variants. Next in-frame start position is after 85 codons. Genomic position: 25801112. Lost 0.143 part of the original CDS.
• PS1: Another start lost variant in NM_020451.3 (SELENON) was described as [Likely_pathogenic] in ClinVar as 373075
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-25800232-T-G is Pathogenic according to our data. Variant chr1-25800232-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 461632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3	c.2T>G	p.Met1?	start_lost	Exon 1 of 13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.2T>G	p.Met1?	start_lost	Exon 1 of 12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.2T>G	p.Met1?	start_lost	Exon 1 of 13	1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1	c.2T>G	p.Met1?	start_lost	Exon 1 of 12	5		ENSP00000363434.1
SELENON	ENST00000354177.9	c.2T>G	p.Met1?	start_lost	Exon 1 of 12	5		ENSP00000346109.5
SELENON	ENST00000494537.2	n.2T>G		non_coding_transcript_exon_variant	Exon 1 of 13	3		ENSP00000508308.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000159 AC: 1 AN: 628544 Hom.: 0 Cov.: 8 AF XY: 0.00000342 AC XY: 1 AN XY: 292422

African (AFR) AF: 0.00 AC: 0 AN: 11876

American (AMR) AF: 0.00 AC: 0 AN: 724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3866

East Asian (EAS) AF: 0.00 AC: 0 AN: 2686

South Asian (SAS) AF: 0.00 AC: 0 AN: 13106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1248

European-Non Finnish (NFE) AF: 0.00000174 AC: 1 AN: 574274

Other (OTH) AF: 0.00 AC: 0 AN: 20550

GnomAD4 genome Cov.: 30

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:2

Aug 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SELENON c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in-frame methionine is at codon 85, and there are several pathogenic variants reported upstream of this codon. The variant was absent in 24144 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2T>G has been reported in the literature in at least one individual affected with Selenon-associated Muscular Dystrophy (Vill_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 461632). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Aug 14, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disruption of initiator codon variants have been observed in individuals affected with clinical features of SEPN1-related disorders (PMID: 1219264, 23394784, 16779558). ClinVar contains an entry for this variant (Variation ID: 461632). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. For these reasons, this variant has been classified as Pathogenic. This sequence change affects the initiator methionine of the SEPN1 mRNA. The next in-frame methionine is located at codon 85. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.083	.;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.034	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	-0.11	T
PhyloP100		-1.6
PROVEAN	Benign	-0.49	N;N;N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.68, 0.78	.;P;P
Vest4		0.27
MutPred		0.99		Gain of methylation at M1 (P = 2e-04);Gain of methylation at M1 (P = 2e-04);Gain of methylation at M1 (P = 2e-04);
MVP		0.93
ClinPred		0.97	D
GERP RS		2.0
PromoterAI		-0.44	Neutral
Varity_R		0.95
Mutation Taster		=5/195	disease causing (ClinVar)

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: rs1174570887; hg19: chr1-26126723;