1-25808592-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020451.3(SELENON):​c.550G>C​(p.Ala184Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00049 in 1,613,288 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A184T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 33)
Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

SELENON
NM_020451.3 missense

Scores

3
4
10

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:5

Conservation

PhyloP100: 2.49
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010834575).
BP6
Variant 1-25808592-G-C is Benign according to our data. Variant chr1-25808592-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 297024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00264 (401/151828) while in subpopulation AFR AF= 0.00904 (374/41394). AF 95% confidence interval is 0.00828. There are 2 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SELENONNM_020451.3 linkc.550G>C p.Ala184Pro missense_variant Exon 5 of 13 ENST00000361547.7 NP_065184.2 Q9NZV5-1
SELENONNM_206926.2 linkc.448G>C p.Ala150Pro missense_variant Exon 4 of 12 NP_996809.1 Q9NZV5-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SELENONENST00000361547.7 linkc.550G>C p.Ala184Pro missense_variant Exon 5 of 13 1 NM_020451.3 ENSP00000355141.2 Q9NZV5-1
SELENONENST00000374315.1 linkc.448G>C p.Ala150Pro missense_variant Exon 4 of 12 5 ENSP00000363434.1 Q9NZV5-2
SELENONENST00000354177.9 linkc.448G>C p.Ala150Pro missense_variant Exon 4 of 12 5 ENSP00000346109.5 H9KV50
SELENONENST00000494537.2 linkn.448G>C non_coding_transcript_exon_variant Exon 4 of 13 3 ENSP00000508308.1 A0A804HLD6

Frequencies

GnomAD3 genomes
AF:
0.00261
AC:
396
AN:
151708
Hom.:
2
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00894
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00157
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:
0.0000295
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000694
AC:
172
AN:
247778
Hom.:
0
AF XY:
0.000468
AC XY:
63
AN XY:
134628
show subpopulations
Gnomad AFR exome
AF:
0.00984
Gnomad AMR exome
AF:
0.000377
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000358
Gnomad OTH exome
AF:
0.000331
GnomAD4 exome
AF:
0.000267
AC:
390
AN:
1461460
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
156
AN XY:
727036
show subpopulations
Gnomad4 AFR exome
AF:
0.00938
Gnomad4 AMR exome
AF:
0.000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.000762
GnomAD4 genome
AF:
0.00264
AC:
401
AN:
151828
Hom.:
2
Cov.:
33
AF XY:
0.00249
AC XY:
185
AN XY:
74204
show subpopulations
Gnomad4 AFR
AF:
0.00904
Gnomad4 AMR
AF:
0.00157
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000295
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000246
Hom.:
0
Bravo
AF:
0.00308
ESP6500AA
AF:
0.00754
AC:
31
ESP6500EA
AF:
0.000119
AC:
1
ExAC
AF:
0.000819
AC:
99
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Uncertain:1Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 09, 2018
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:2
Aug 26, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

SELENON-related disorder Benign:1
Apr 14, 2021
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

SEPN1-related disorder Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.037
T
BayesDel_noAF
Pathogenic
0.29
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Benign
0.11
.;T;.
Eigen
Benign
0.11
Eigen_PC
Benign
0.092
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.74
T;T;T
MetaRNN
Benign
0.011
T;T;T
MetaSVM
Uncertain
0.22
D
MutationAssessor
Benign
1.7
.;L;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-1.4
N;N;N
REVEL
Pathogenic
0.71
Sift
Benign
0.046
D;D;D
Sift4G
Benign
0.13
T;T;T
Polyphen
0.91, 0.95
.;P;P
Vest4
0.54
MVP
0.94
MPC
0.31
ClinPred
0.036
T
GERP RS
4.5
Varity_R
0.22

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199742668; hg19: chr1-26135083; API