1-25808435-C-G

Variant names:

• chr1-25808435-C-G
• rs4659382
• NM_020451.3:c.538-145C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020451.3(SELENON):​c.538-145C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 872,964 control chromosomes in the GnomAD database, including 27,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.20 (3774 hom., cov: 32)
  • Exomes 𝑓: 0.25 (23826 hom.)
• Consequence: SELENON NM_020451.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.60
• Publications: 8 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-25808435-C-G is Benign according to our data. Variant chr1-25808435-C-G is described in ClinVar as Benign. ClinVar VariationId is 1262044.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3	c.538-145C>G		intron_variant	Intron 4 of 12	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.436-145C>G		intron_variant	Intron 3 of 11		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.538-145C>G		intron_variant	Intron 4 of 12	1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1	c.436-145C>G		intron_variant	Intron 3 of 11	5		ENSP00000363434.1
SELENON	ENST00000354177.9	c.436-145C>G		intron_variant	Intron 3 of 11	5		ENSP00000346109.5
SELENON	ENST00000494537.2	n.436-145C>G		intron_variant	Intron 3 of 12	3		ENSP00000508308.1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30583 AN: 152014 Hom.: 3773 Cov.: 32

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.249 AC: 179744 AN: 720832 Hom.: 23826 AF XY: 0.246 AC XY: 92538 AN XY: 375758

African (AFR) AF: 0.0583 AC: 1097 AN: 18808

American (AMR) AF: 0.204 AC: 7135 AN: 34890

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 5500 AN: 17318

East Asian (EAS) AF: 0.371 AC: 13130 AN: 35430

South Asian (SAS) AF: 0.160 AC: 9843 AN: 61444

European-Finnish (FIN) AF: 0.269 AC: 12948 AN: 48152

Middle Eastern (MID) AF: 0.294 AC: 725 AN: 2462

European-Non Finnish (NFE) AF: 0.259 AC: 120849 AN: 467218

Other (OTH) AF: 0.243 AC: 8517 AN: 35110

GnomAD4 genome AF: 0.201 AC: 30572 AN: 152132 Hom.: 3774 Cov.: 32 AF XY: 0.202 AC XY: 15010 AN XY: 74348

African (AFR) AF: 0.0620 AC: 2575 AN: 41542

American (AMR) AF: 0.199 AC: 3047 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 1132 AN: 3468

East Asian (EAS) AF: 0.343 AC: 1775 AN: 5170

South Asian (SAS) AF: 0.158 AC: 762 AN: 4818

European-Finnish (FIN) AF: 0.275 AC: 2912 AN: 10600

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17442 AN: 67928

Other (OTH) AF: 0.233 AC: 493 AN: 2114

Alfa AF: 0.125 Hom.: 242

Bravo AF: 0.198

Asia WGS AF: 0.185 AC: 634 AN: 3444

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.056
DANN	Benign	0.39
PhyloP100		-2.6
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: rs4659382; hg19: chr1-26134926; COSMIC: COSV62525908; COSMIC: COSV62525908;