chr1-25800232-T-G

Position:

• chr1-25800232-T-G

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>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

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-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. Variant chr1-25800232-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3	c.2T>G	p.Met1?	start_lost	1/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.2T>G	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>G	p.Met1?	start_lost	1/13	1	NM_020451.3	ENSP00000355141
SELENON	ENST00000374315.1	c.2T>G	p.Met1?	start_lost	1/12	5		ENSP00000363434	P1
SELENON	ENST00000354177.9	c.2T>G	p.Met1?	start_lost	1/12	5		ENSP00000346109
SELENON	ENST00000494537.2	c.2T>G	p.Met1?	start_lost, NMD_transcript_variant	1/13	3		ENSP00000508308

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000174

Gnomad4 OTH exome AF: 0.00

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 13, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 14, 2020	This sequence change affects the initiator methionine of the SEPN1 mRNA. The next in-frame methionine is located at codon 85. For these reasons, this variant has been classified as Pathogenic. 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. -

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
MutationTaster	Benign	1.0	D;D;D
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
Varity_R		0.95

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;