NM_001008212.2:c.293T>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001008212.2(OPTN):​c.293T>A​(p.Met98Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,614,026 control chromosomes in the GnomAD database, including 1,623 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.059 ( 376 hom., cov: 32)
Exomes 𝑓: 0.035 ( 1247 hom. )

Consequence

OPTN
NM_001008212.2 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:14O:1

Conservation

PhyloP100: 0.0630
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0016944706).
BP6
Variant 10-13110400-T-A is Benign according to our data. Variant chr10-13110400-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 7099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-13110400-T-A is described in Lovd as [Likely_benign]. Variant chr10-13110400-T-A is described in Lovd as [Benign]. Variant chr10-13110400-T-A is described in Lovd as [Pathogenic].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OPTNNM_001008212.2 linkc.293T>A p.Met98Lys missense_variant Exon 4 of 15 ENST00000378747.8 NP_001008213.1 Q96CV9-1
OPTNNM_001008211.1 linkc.293T>A p.Met98Lys missense_variant Exon 5 of 16 NP_001008212.1 Q96CV9-1
OPTNNM_001008213.1 linkc.293T>A p.Met98Lys missense_variant Exon 5 of 16 NP_001008214.1 Q96CV9-1
OPTNNM_021980.4 linkc.293T>A p.Met98Lys missense_variant Exon 3 of 14 NP_068815.2 Q96CV9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OPTNENST00000378747.8 linkc.293T>A p.Met98Lys missense_variant Exon 4 of 15 1 NM_001008212.2 ENSP00000368021.3 Q96CV9-1

Frequencies

GnomAD3 genomes
AF:
0.0591
AC:
8982
AN:
152102
Hom.:
373
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.119
Gnomad AMI
AF:
0.0417
Gnomad AMR
AF:
0.0298
Gnomad ASJ
AF:
0.0711
Gnomad EAS
AF:
0.135
Gnomad SAS
AF:
0.0519
Gnomad FIN
AF:
0.0289
Gnomad MID
AF:
0.0506
Gnomad NFE
AF:
0.0280
Gnomad OTH
AF:
0.0578
GnomAD3 exomes
AF:
0.0442
AC:
11112
AN:
251306
Hom.:
417
AF XY:
0.0430
AC XY:
5846
AN XY:
135850
show subpopulations
Gnomad AFR exome
AF:
0.120
Gnomad AMR exome
AF:
0.0198
Gnomad ASJ exome
AF:
0.0727
Gnomad EAS exome
AF:
0.126
Gnomad SAS exome
AF:
0.0471
Gnomad FIN exome
AF:
0.0257
Gnomad NFE exome
AF:
0.0280
Gnomad OTH exome
AF:
0.0437
GnomAD4 exome
AF:
0.0348
AC:
50846
AN:
1461806
Hom.:
1247
Cov.:
33
AF XY:
0.0351
AC XY:
25532
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.121
Gnomad4 AMR exome
AF:
0.0211
Gnomad4 ASJ exome
AF:
0.0711
Gnomad4 EAS exome
AF:
0.0983
Gnomad4 SAS exome
AF:
0.0491
Gnomad4 FIN exome
AF:
0.0251
Gnomad4 NFE exome
AF:
0.0281
Gnomad4 OTH exome
AF:
0.0485
GnomAD4 genome
AF:
0.0590
AC:
8982
AN:
152220
Hom.:
376
Cov.:
32
AF XY:
0.0593
AC XY:
4413
AN XY:
74414
show subpopulations
Gnomad4 AFR
AF:
0.119
Gnomad4 AMR
AF:
0.0298
Gnomad4 ASJ
AF:
0.0711
Gnomad4 EAS
AF:
0.135
Gnomad4 SAS
AF:
0.0516
Gnomad4 FIN
AF:
0.0289
Gnomad4 NFE
AF:
0.0280
Gnomad4 OTH
AF:
0.0567
Alfa
AF:
0.0381
Hom.:
126
Bravo
AF:
0.0618
TwinsUK
AF:
0.0345
AC:
128
ALSPAC
AF:
0.0280
AC:
108
ESP6500AA
AF:
0.118
AC:
518
ESP6500EA
AF:
0.0322
AC:
277
ExAC
AF:
0.0449
AC:
5451
Asia WGS
AF:
0.0990
AC:
345
AN:
3478
EpiCase
AF:
0.0309
EpiControl
AF:
0.0310

ClinVar

Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Benign:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 08, 2014
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:4
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Sep 12, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16358725, 17361544, 31198474, 31182772, 17293779, 28430856, 26376340, 25681989, 15226658, 11834836, 19172505, 17122126, 23357852) -

-
Clinical Genetics, Academic Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 29, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary open angle glaucoma Benign:2
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Glaucoma 1, open angle, E Pathogenic:1
Feb 08, 2002
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Amyotrophic lateral sclerosis type 12 Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Primary open angle glaucoma;C1842026:Glaucoma 1, open angle, E;C3150692:Amyotrophic lateral sclerosis type 12 Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary open angle glaucoma;C1847730:Glaucoma, normal tension, susceptibility to;C3150692:Amyotrophic lateral sclerosis type 12 Benign:1
Feb 25, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Glaucoma, normal tension, susceptibility to Other:1
Feb 08, 2002
OMIM
Significance: risk factor
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
4.8
DANN
Benign
0.64
DEOGEN2
Benign
0.14
T;.;T;.;T;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.88
FATHMM_MKL
Benign
0.047
N
LIST_S2
Benign
0.57
.;.;.;T;.;T
MetaRNN
Benign
0.0017
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
N;N;N;N;N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.060
N;N;N;N;N;N
REVEL
Benign
0.22
Sift
Benign
0.93
T;T;T;T;T;T
Sift4G
Benign
0.90
T;T;T;T;T;T
Polyphen
0.0010
B;B;B;B;B;B
Vest4
0.081
MPC
0.27
ClinPred
0.00087
T
GERP RS
3.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.20
gMVP
0.17

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: rs11258194; hg19: chr10-13152400; COSMIC: COSV53809711; COSMIC: COSV53809711; API