rs11258194

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:15O:1

Conservation

PhyloP100: 0.0630

Publications

126 publications found

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]

OPTN Gene-Disease associations (from GenCC):

glaucoma, normal tension, susceptibility to
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
amyotrophic lateral sclerosis type 12
Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
glaucoma 1, open angle, E
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

OPTN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 7099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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
OPTN	NM_001008212.2 link	c.293T>A	p.Met98Lys	missense_variant	Exon 4 of 15	ENST00000378747.8	NP_001008213.1	Q96CV9-1
OPTN	NM_001008211.1 link	c.293T>A	p.Met98Lys	missense_variant	Exon 5 of 16		NP_001008212.1	Q96CV9-1
OPTN	NM_001008213.1 link	c.293T>A	p.Met98Lys	missense_variant	Exon 5 of 16		NP_001008214.1	Q96CV9-1
OPTN	NM_021980.4 link	c.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
OPTN	ENST00000378747.8 link	c.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.:

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

GnomAD2 exomes

AF:

0.0442

AC:

11112

AN:

251306

AF XY:

0.0430

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 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.:

AF XY:

0.0351

AC XY:

25532

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.121

AC:

4065

AN:

33480

American (AMR)

AF:

0.0211

AC:

942

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0711

AC:

1859

AN:

26134

East Asian (EAS)

AF:

0.0983

AC:

3903

AN:

39698

South Asian (SAS)

AF:

0.0491

AC:

4239

AN:

86252

European-Finnish (FIN)

AF:

0.0251

AC:

1339

AN:

53402

Middle Eastern (MID)

AF:

0.0600

AC:

346

AN:

5768

European-Non Finnish (NFE)

AF:

0.0281

AC:

31226

AN:

1111960

Other (OTH)

AF:

0.0485

AC:

2927

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2821

5642

8462

11283

14104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1326

2652

3978

5304

6630

<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

AF:

0.0590

AC:

8982

AN:

152220

Hom.:

376

Cov.:

AF XY:

0.0593

AC XY:

4413

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.119

AC:

4950

AN:

41502

American (AMR)

AF:

0.0298

AC:

455

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0711

AC:

247

AN:

3472

East Asian (EAS)

AF:

0.135

AC:

697

AN:

5168

South Asian (SAS)

AF:

0.0516

AC:

249

AN:

4828

European-Finnish (FIN)

AF:

0.0289

AC:

306

AN:

10606

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0280

AC:

1906

AN:

68030

Other (OTH)

AF:

0.0567

AC:

120

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

433

865

1298

1730

2163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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;C3150692:Amyotrophic lateral sclerosis type 12

Benign:1

Feb 05, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

BayesDel_noAF

Benign

-0.32

CADD

Benign

4.8

(source)

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

LIST_S2

Benign

0.57

.;.;.;T;.;T

MetaRNN

Benign

0.0017

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;N;N;N;N

PhyloP100

0.063

PrimateAI

Benign

0.31

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

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.17

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over