rs760598

Variant names:

• chr1-25811645-C-A
• rs760598
• NM_020451.3:c.1093-46C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-25811645-C-A
• chr1-25811645-C-G
• chr1-25811645-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020451.3(SELENON):​c.1093-46C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 1,608,850 control chromosomes in the GnomAD database, including 481,014 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38906 hom., cov: 32)
  • Exomes 𝑓: 0.78 (442108 hom.)
• Consequence: SELENON NM_020451.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.911
• Publications: 10 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

ENSG00000255054 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-25811645-C-A is Benign according to our data. Variant chr1-25811645-C-A is described in ClinVar as Benign. ClinVar VariationId is 261271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	NM_020451.3	MANE Select	c.1093-46C>A		intron	N/A	NP_065184.2
	SELENON	NM_206926.2		c.991-46C>A		intron	N/A	NP_996809.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	ENST00000361547.7	TSL:1 MANE Select	c.1093-46C>A		intron	N/A	ENSP00000355141.2
	SELENON	ENST00000374315.1	TSL:5	c.991-46C>A		intron	N/A	ENSP00000363434.1
	SELENON	ENST00000354177.9	TSL:5	c.922-46C>A		intron	N/A	ENSP00000346109.5

Frequencies

GnomAD3 genomes AF: 0.699 AC: 106247 AN: 151984 Hom.: 38885 Cov.: 32

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.931

Gnomad AMR AF: 0.804

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.966

Gnomad SAS AF: 0.886

Gnomad FIN AF: 0.753

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.766

Gnomad OTH AF: 0.726

GnomAD2 exomes AF: 0.790 AC: 194529 AN: 246134 AF XY: 0.795

Gnomad AFR exome AF: 0.460

Gnomad AMR exome AF: 0.880

Gnomad ASJ exome AF: 0.765

Gnomad EAS exome AF: 0.965

Gnomad FIN exome AF: 0.742

Gnomad NFE exome AF: 0.768

Gnomad OTH exome AF: 0.794

GnomAD4 exome AF: 0.776 AC: 1130371 AN: 1456748 Hom.: 442108 Cov.: 32 AF XY: 0.780 AC XY: 565250 AN XY: 724996

African (AFR) AF: 0.461 AC: 15402 AN: 33394

American (AMR) AF: 0.873 AC: 38923 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 19916 AN: 26100

East Asian (EAS) AF: 0.961 AC: 38106 AN: 39672

South Asian (SAS) AF: 0.875 AC: 75409 AN: 86164

European-Finnish (FIN) AF: 0.743 AC: 39556 AN: 53268

Middle Eastern (MID) AF: 0.809 AC: 4654 AN: 5756

European-Non Finnish (NFE) AF: 0.769 AC: 851957 AN: 1107600

Other (OTH) AF: 0.771 AC: 46448 AN: 60220

GnomAD4 genome AF: 0.699 AC: 106303 AN: 152102 Hom.: 38906 Cov.: 32 AF XY: 0.705 AC XY: 52430 AN XY: 74338

African (AFR) AF: 0.469 AC: 19460 AN: 41500

American (AMR) AF: 0.805 AC: 12307 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 2638 AN: 3470

East Asian (EAS) AF: 0.966 AC: 4976 AN: 5152

South Asian (SAS) AF: 0.885 AC: 4263 AN: 4816

European-Finnish (FIN) AF: 0.753 AC: 7975 AN: 10586

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.766 AC: 52046 AN: 67968

Other (OTH) AF: 0.728 AC: 1537 AN: 2112

Alfa AF: 0.755 Hom.: 58257

Bravo AF: 0.694

Asia WGS AF: 0.893 AC: 3108 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Eichsfeld type congenital muscular dystrophy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.3
DANN	Benign	0.87
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism (auto)

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: rs760598; hg19: chr1-26138136;