Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001008212.2(OPTN):c.1634G>A(p.Arg545Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,614,042 control chromosomes in the GnomAD database, including 36 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R545W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 30 hom. )

Consequence

OPTN
NM_001008212.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:9

Conservation

PhyloP100: -1.60

Publications

62 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03974253).

BP6

Variant 10-13136766-G-A is Benign according to our data. Variant chr10-13136766-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7098.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00144 (219/152268) while in subpopulation EAS AF = 0.0338 (175/5176). AF 95% confidence interval is 0.0297. There are 6 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008212.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OPTN	NM_001008212.2	MANE Select	c.1634G>A	p.Arg545Gln	missense	Exon 15 of 15	NP_001008213.1
OPTN	NM_001008211.1		c.1634G>A	p.Arg545Gln	missense	Exon 16 of 16	NP_001008212.1
OPTN	NM_001008213.1		c.1634G>A	p.Arg545Gln	missense	Exon 16 of 16	NP_001008214.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OPTN	ENST00000378747.8	TSL:1 MANE Select	c.1634G>A	p.Arg545Gln	missense	Exon 15 of 15	ENSP00000368021.3
OPTN	ENST00000378748.7	TSL:1	c.1634G>A	p.Arg545Gln	missense	Exon 16 of 16	ENSP00000368022.3
OPTN	ENST00000378757.6	TSL:1	c.1634G>A	p.Arg545Gln	missense	Exon 14 of 14	ENSP00000368032.2

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

219

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0337

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00310

AC:

780

AN:

251396

AF XY:

0.00297

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00437

Gnomad EAS exome

AF:

0.0345

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00137

AC:

1998

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

982

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.000246

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00406

AC:

106

AN:

26132

East Asian (EAS)

AF:

0.0349

AC:

1387

AN:

39698

South Asian (SAS)

AF:

0.00161

AC:

139

AN:

86248

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000122

AC:

136

AN:

1111932

Other (OTH)

AF:

0.00348

AC:

210

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

113

226

339

452

565

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00144

AC:

219

AN:

152268

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

130

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41552

American (AMR)

AF:

0.000262

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.0338

AC:

175

AN:

5176

South Asian (SAS)

AF:

0.00249

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68018

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00117

Hom.:

Bravo

AF:

0.00162

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00290

AC:

352

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary open angle glaucoma (3)

Amyotrophic lateral sclerosis type 12 (2)

not provided (2)

Glaucoma 1, open angle, E (1)

not specified (1)

OPTN-related disorder (1)

Primary open angle glaucoma;C1842026:Glaucoma 1, open angle, E;C3150692:Amyotrophic lateral sclerosis type 12 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.0030

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.063

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.68

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.88

MutationAssessor

Benign

-1.6

PhyloP100

-1.6

PrimateAI

Benign

0.22

PROVEAN

Benign

1.5

REVEL

Benign

0.22

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.12

MVP

0.81

MPC

0.20

ClinPred

0.016

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.013

gMVP

0.21

Mutation Taster

=100/0

polymorphism

(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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rs75654767

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over