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rs113955718

chr10-13112485-C-Achr10-13112485-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001008212.2(OPTN):c.402C>A(p.Ala134=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,898 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A134A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0073 ( 18 hom., cov: 31)
Exomes 𝑓: 0.00077 ( 12 hom. )

Consequence

OPTN
NM_001008212.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.229
Variant links:
Genes affected
OPTN (HGNC:17142): (optineurin) This gene encodes the coiled-coil containing protein optineurin. Optineurin may play a role in normal-tension glaucoma and adult-onset primary open angle glaucoma. Optineurin interacts with adenovirus E3-14.7K protein and may utilize tumor necrosis factor-alpha or Fas-ligand pathways to mediate apoptosis, inflammation or vasoconstriction. Optineurin may also function in cellular morphogenesis and membrane trafficking, vesicle trafficking, and transcription activation through its interactions with the RAB8, huntingtin, and transcription factor IIIA proteins. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 10-13112485-C-A is Benign according to our data. Variant chr10-13112485-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 299210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-13112485-C-A is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.229 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00728 (1107/152016) while in subpopulation AFR AF= 0.0252 (1046/41438). AF 95% confidence interval is 0.024. There are 18 homozygotes in gnomad4. There are 513 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 18 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
OPTNNM_001008212.2 linkuse as main transcriptc.402C>A p.Ala134= synonymous_variant 5/15 ENST00000378747.8
OPTNNM_001008211.1 linkuse as main transcriptc.402C>A p.Ala134= synonymous_variant 6/16
OPTNNM_001008213.1 linkuse as main transcriptc.402C>A p.Ala134= synonymous_variant 6/16
OPTNNM_021980.4 linkuse as main transcriptc.402C>A p.Ala134= synonymous_variant 4/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
OPTNENST00000378747.8 linkuse as main transcriptc.402C>A p.Ala134= synonymous_variant 5/151 NM_001008212.2 P3Q96CV9-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00725
AC:
1102
AN:
151898
Hom.:
18
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0252
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00256
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00670
GnomAD3 exomes
AF:
0.00196
AC:
492
AN:
251438
Hom.:
6
AF XY:
0.00141
AC XY:
191
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.0254
Gnomad AMR exome
AF:
0.00139
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.000693
Gnomad NFE exome
AF:
0.0000879
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000768
AC:
1123
AN:
1461882
Hom.:
12
Cov.:
32
AF XY:
0.000635
AC XY:
462
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0252
Gnomad4 AMR exome
AF:
0.00179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.000412
Gnomad4 NFE exome
AF:
0.0000405
Gnomad4 OTH exome
AF:
0.00199
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00728
AC:
1107
AN:
152016
Hom.:
18
Cov.:
31
AF XY:
0.00690
AC XY:
513
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0252
Gnomad4 AMR
AF:
0.00255
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00664
Alfa
AF:
0.00325
Hom.:
2
Bravo
AF:
0.00818
Asia WGS
AF:
0.00231
AC:
8
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsDec 21, 2017- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJan 12, 2021- -
Amyotrophic lateral sclerosis type 12 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 11, 2019This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Primary open angle glaucoma;C1842026:Glaucoma 1, open angle, E;C3150692:Amyotrophic lateral sclerosis type 12 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 27, 2024- -
Primary open angle glaucoma;C1847730:Glaucoma, normal tension, susceptibility to;C3150692:Amyotrophic lateral sclerosis type 12 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 15, 2021- -
Primary open angle glaucoma Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.72
Cadd
Benign
0.48
Dann
Benign
0.31
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs113955718; hg19: chr10-13154485; API