1-25800195-TTCCCGGGCCGCCGGCAGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCC-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePP5_Moderate

The NM_020451.3(SELENON):​c.-30_64delGGCCGCCGGCAGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCG​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000043 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SELENON
NM_020451.3 frameshift, start_lost

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.881

Publications

0 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 92 pathogenic variants in the truncated region.
PS1
Another start lost variant in NM_020451.3 (SELENON) was described as [Likely_pathogenic] in ClinVar as 373075
PP5
Variant 1-25800195-TTCCCGGGCCGCCGGCAGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCC-T is Pathogenic according to our data. Variant chr1-25800195-TTCCCGGGCCGCCGGCAGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCC-T is described in ClinVar as [Pathogenic]. Clinvar id is 2418838.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SELENONNM_020451.3 linkc.-30_64delGGCCGCCGGCAGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCG p.Met1fs frameshift_variant, start_lost Exon 1 of 13 ENST00000361547.7 NP_065184.2 Q9NZV5-1
SELENONNM_020451.3 linkc.-30_64delGGCCGCCGGCAGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCG 5_prime_UTR_variant Exon 1 of 13 ENST00000361547.7 NP_065184.2 Q9NZV5-1
SELENONNM_206926.2 linkc.-30_64delGGCCGCCGGCAGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCG p.Met1fs frameshift_variant, start_lost Exon 1 of 12 NP_996809.1 Q9NZV5-2
SELENONNM_206926.2 linkc.-30_64delGGCCGCCGGCAGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCG 5_prime_UTR_variant Exon 1 of 12 NP_996809.1 Q9NZV5-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SELENONENST00000361547.7 linkc.-30_64delGGCCGCCGGCAGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCG p.Met1fs frameshift_variant, start_lost Exon 1 of 13 1 NM_020451.3 ENSP00000355141.2 Q9NZV5-1
SELENONENST00000361547.7 linkc.-30_64delGGCCGCCGGCAGCCGCCGCCAGCCGCAGCCATGGGCCGGGCCCGGCCGGGCCAACGCGGGCCGCCCAGCCCCGGCCCCGCCGCGCAGCCTCCCG 5_prime_UTR_variant Exon 1 of 13 1 NM_020451.3 ENSP00000355141.2 Q9NZV5-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
142028
Hom.:
0
Cov.:
30
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000434
AC:
8
AN:
184158
Hom.:
0
AF XY:
0.0000575
AC XY:
5
AN XY:
86910
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
3598
American (AMR)
AF:
0.00
AC:
0
AN:
210
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
1062
East Asian (EAS)
AF:
0.00
AC:
0
AN:
774
South Asian (SAS)
AF:
0.00
AC:
0
AN:
3972
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
62
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
334
European-Non Finnish (NFE)
AF:
0.0000476
AC:
8
AN:
168050
Other (OTH)
AF:
0.00
AC:
0
AN:
6096
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
142028
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
68888
African (AFR)
AF:
0.00
AC:
0
AN:
39386
American (AMR)
AF:
0.00
AC:
0
AN:
14496
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3334
East Asian (EAS)
AF:
0.00
AC:
0
AN:
4894
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4646
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
7724
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
296
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
64386
Other (OTH)
AF:
0.00
AC:
0
AN:
1990

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Pathogenic:1
Feb 11, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant is also known as c.-34_60del. Disruption of the initiator codon has been observed in individuals with SELENON-related conditions (PMID: 12192640, 21670436, 23394784, 28558865). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change affects the initiator methionine of the SELENON mRNA. The next in-frame methionine is located at codon 85. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.88
Mutation Taster
=40/160
disease causing (long InDel)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

hg19: chr1-26126686; API