dbSNP rs2234968: OPTN:p.Thr34Thr (chr10-13109224-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001008212.2(OPTN):c.102G>A(p.Thr34Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,613,578 control chromosomes in the GnomAD database, including 53,239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3653 hom., cov: 30)

Exomes 𝑓: 0.26 ( 49586 hom. )

Consequence

OPTN
NM_001008212.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -3.19

Publications

57 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: SD, AR, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, Laboratory for Molecular Medicine
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 10-13109224-G-A is Benign according to our data. Variant chr10-13109224-G-A is described in ClinVar as Benign. ClinVar VariationId is 96022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.19 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

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	UniProt
OPTN	NM_001008212.2	MANE Select	c.102G>A	p.Thr34Thr	synonymous	Exon 3 of 15	NP_001008213.1	Q96CV9-1
OPTN	NM_001008211.1		c.102G>A	p.Thr34Thr	synonymous	Exon 4 of 16	NP_001008212.1	Q96CV9-1
OPTN	NM_001008213.1		c.102G>A	p.Thr34Thr	synonymous	Exon 4 of 16	NP_001008214.1	Q96CV9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OPTN	ENST00000378747.8	TSL:1 MANE Select	c.102G>A	p.Thr34Thr	synonymous	Exon 3 of 15	ENSP00000368021.3	Q96CV9-1
OPTN	ENST00000378748.7	TSL:1	c.102G>A	p.Thr34Thr	synonymous	Exon 4 of 16	ENSP00000368022.3	Q96CV9-1
OPTN	ENST00000378757.6	TSL:1	c.102G>A	p.Thr34Thr	synonymous	Exon 2 of 14	ENSP00000368032.2	Q96CV9-1

Frequencies

GnomAD3 genomes

AF:

0.199

AC:

30209

AN:

151882

Hom.:

3651

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0535

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.255

Gnomad ASJ

AF:

0.320

Gnomad EAS

AF:

0.187

Gnomad SAS

AF:

0.235

Gnomad FIN

AF:

0.182

Gnomad MID

AF:

0.312

Gnomad NFE

AF:

0.269

Gnomad OTH

AF:

0.235

GnomAD2 exomes

AF:

0.242

AC:

60876

AN:

251260

AF XY:

0.244

show subpopulations

Gnomad AFR exome

AF:

0.0479

Gnomad AMR exome

AF:

0.283

Gnomad ASJ exome

AF:

0.329

Gnomad EAS exome

AF:

0.202

Gnomad FIN exome

AF:

0.179

Gnomad NFE exome

AF:

0.273

Gnomad OTH exome

AF:

0.260

GnomAD4 exome

AF:

0.256

AC:

374781

AN:

1461578

Hom.:

49586

Cov.:

AF XY:

0.256

AC XY:

186429

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.0443

AC:

1482

AN:

33478

American (AMR)

AF:

0.278

AC:

12444

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.329

AC:

8599

AN:

26136

East Asian (EAS)

AF:

0.187

AC:

7433

AN:

39700

South Asian (SAS)

AF:

0.221

AC:

19104

AN:

86254

European-Finnish (FIN)

AF:

0.187

AC:

9963

AN:

53370

Middle Eastern (MID)

AF:

0.296

AC:

1710

AN:

5768

European-Non Finnish (NFE)

AF:

0.269

AC:

298939

AN:

1111774

Other (OTH)

AF:

0.250

AC:

15107

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

15432

30865

46297

61730

77162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9882

19764

29646

39528

49410

<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:

0.199

AC:

30209

AN:

152000

Hom.:

3653

Cov.:

AF XY:

0.197

AC XY:

14651

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.0533

AC:

2214

AN:

41528

American (AMR)

AF:

0.255

AC:

3896

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.320

AC:

1112

AN:

3472

East Asian (EAS)

AF:

0.187

AC:

964

AN:

5146

South Asian (SAS)

AF:

0.234

AC:

1122

AN:

4788

European-Finnish (FIN)

AF:

0.182

AC:

1922

AN:

10564

Middle Eastern (MID)

AF:

0.312

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.269

AC:

18290

AN:

67920

Other (OTH)

AF:

0.237

AC:

502

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1147

2293

3440

4586

5733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

324

648

972

1296

1620

<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:

0.246

Hom.:

16413

Bravo

AF:

0.199

Asia WGS

AF:

0.210

AC:

731

AN:

3478

EpiCase

AF:

0.284

EpiControl

AF:

0.283

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (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

-0.79

CADD

Benign

0.70

(source)

DANN

Benign

0.78

PhyloP100

-3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over