rs11258194

Positions:

chr10-13110400-T-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

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]

OPTN links:

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=0.0016944706).

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/exons	MANE	Protein	UniProt
OPTN	NM_001008212.2 linkuse as main transcript	c.293T>A	p.Met98Lys	missense_variant	4/15	ENST00000378747.8	NP_001008213.1	Q96CV9-1
OPTN	NM_001008211.1 linkuse as main transcript	c.293T>A	p.Met98Lys	missense_variant	5/16		NP_001008212.1	Q96CV9-1
OPTN	NM_001008213.1 linkuse as main transcript	c.293T>A	p.Met98Lys	missense_variant	5/16		NP_001008214.1	Q96CV9-1
OPTN	NM_021980.4 linkuse as main transcript	c.293T>A	p.Met98Lys	missense_variant	3/14		NP_068815.2	Q96CV9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPTN	ENST00000378747.8 linkuse as main transcript	c.293T>A	p.Met98Lys	missense_variant	4/15	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

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.:

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.:

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

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2014	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2018	This variant is associated with the following publications: (PMID: 16358725, 17361544, 31198474, 31182772, 17293779, 28430856, 26376340, 25681989, 15226658, 11834836, 19172505, 17122126, 23357852) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Primary open angle glaucoma

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Glaucoma 1, open angle, E

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 08, 2002

- -

Amyotrophic lateral sclerosis type 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Primary open angle glaucoma;C1847730:Glaucoma, normal tension, susceptibility to;C3150692:Amyotrophic lateral sclerosis type 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 25, 2022

- -

Glaucoma, normal tension, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 08, 2002

- -

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

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

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over