1-25811541-C-G

Variant names:

• chr1-25811541-C-G
• rs148071754
• NM_020451.3:c.1092+6C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020451.3(SELENON):​c.1092+6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00982 in 1,613,672 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (13 hom., cov: 33)
  • Exomes 𝑓: 0.010 (107 hom.)
• Consequence: SELENON NM_020451.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003976
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0720
• Publications: 2 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, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics
• 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

ENSG00000255054 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-25811541-C-G is Benign according to our data. Variant chr1-25811541-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00732 (1115/152296) while in subpopulation NFE AF = 0.0123 (836/68024). AF 95% confidence interval is 0.0116. There are 13 homozygotes in GnomAd4. There are 520 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020451.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	NM_020451.3	MANE Select	c.1092+6C>G		splice_region intron	N/A	NP_065184.2
	SELENON	NM_206926.2		c.990+6C>G		splice_region intron	N/A	NP_996809.1	Q9NZV5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	ENST00000361547.7	TSL:1 MANE Select	c.1092+6C>G		splice_region intron	N/A	ENSP00000355141.2	Q9NZV5-1
	SELENON	ENST00000374315.1	TSL:5	c.990+6C>G		splice_region intron	N/A	ENSP00000363434.1	Q9NZV5-2
	SELENON	ENST00000354177.9	TSL:5	c.921+6C>G		splice_region intron	N/A	ENSP00000346109.5	H9KV50

Frequencies

GnomAD3 genomes AF: 0.00733 AC: 1115 AN: 152178 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00775 AC: 1934 AN: 249452 AF XY: 0.00811

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00765

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00359

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.0101 AC: 14739 AN: 1461376 Hom.: 107 Cov.: 32 AF XY: 0.0102 AC XY: 7393 AN XY: 727016

African (AFR) AF: 0.00197 AC: 66 AN: 33476

American (AMR) AF: 0.00452 AC: 202 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00666 AC: 174 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00608 AC: 524 AN: 86246

European-Finnish (FIN) AF: 0.00414 AC: 221 AN: 53320

Middle Eastern (MID) AF: 0.0281 AC: 162 AN: 5766

European-Non Finnish (NFE) AF: 0.0116 AC: 12841 AN: 1111630

Other (OTH) AF: 0.00908 AC: 548 AN: 60384

GnomAD4 genome AF: 0.00732 AC: 1115 AN: 152296 Hom.: 13 Cov.: 33 AF XY: 0.00698 AC XY: 520 AN XY: 74472

African (AFR) AF: 0.00188 AC: 78 AN: 41558

American (AMR) AF: 0.00542 AC: 83 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4830

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10614

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 836 AN: 68024

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00806 Hom.: 5

Bravo AF: 0.00724

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0141

EpiControl AF: 0.0134

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Eichsfeld type congenital muscular dystrophy (1)
-	-	1	SEPN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.70
PhyloP100		-0.072
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.026
SpliceAI score (max)		0.050		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: rs148071754; hg19: chr1-26138032;