Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_001008212.2(OPTN):c.489A>G(p.Glu163Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,118 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0019 ( 3 hom. )

Consequence

OPTN
NM_001008212.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.432

Publications

7 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 10-13112572-A-G is Benign according to our data. Variant chr10-13112572-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 256881.

BP7

Synonymous conserved (PhyloP=0.432 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 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.489A>G	p.Glu163Glu	synonymous	Exon 5 of 15	NP_001008213.1
OPTN	NM_001008211.1		c.489A>G	p.Glu163Glu	synonymous	Exon 6 of 16	NP_001008212.1
OPTN	NM_001008213.1		c.489A>G	p.Glu163Glu	synonymous	Exon 6 of 16	NP_001008214.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OPTN	ENST00000378747.8	TSL:1 MANE Select	c.489A>G	p.Glu163Glu	synonymous	Exon 5 of 15	ENSP00000368021.3
OPTN	ENST00000378748.7	TSL:1	c.489A>G	p.Glu163Glu	synonymous	Exon 6 of 16	ENSP00000368022.3
OPTN	ENST00000378757.6	TSL:1	c.489A>G	p.Glu163Glu	synonymous	Exon 4 of 14	ENSP00000368032.2

Frequencies

GnomAD3 genomes

AF:

0.00151

AC:

230

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00157

AC:

394

AN:

251486

AF XY:

0.00176

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.00229

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00189

AC:

2765

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

1351

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33480

American (AMR)

AF:

0.00103

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00314

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00167

AC:

144

AN:

86258

European-Finnish (FIN)

AF:

0.000749

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00204

AC:

2274

AN:

1112006

Other (OTH)

AF:

0.00210

AC:

127

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

152

304

457

609

761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<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:

0.00152

AC:

231

AN:

152230

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41544

American (AMR)

AF:

0.000589

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00244

AC:

166

AN:

68004

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00232

Hom.:

Bravo

AF:

0.00169

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00354

EpiControl

AF:

0.00332

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (2)

Amyotrophic lateral sclerosis type 12 (1)

Primary open angle glaucoma (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

BayesDel_noAF

Benign

-0.65

CADD

Benign

5.7

(source)

DANN

Benign

0.66

PhyloP100

0.43

PromoterAI

-0.0089

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs113811959

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