NM_001008212.2:c.553-5C>T

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.553-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 1,591,242 control chromosomes in the GnomAD database, including 519,174 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.81 ( 49925 hom., cov: 31)

Exomes 𝑓: 0.81 ( 469249 hom. )

Consequence

OPTN
NM_001008212.2 splice_region, intron

Scores

Splicing: ADA: 0.00002316

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.120

Publications

28 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 10-13116262-C-T is Benign according to our data. Variant chr10-13116262-C-T is described in ClinVar as Benign. ClinVar VariationId is 197846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.854 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	Effect	Exon Rank	Protein	UniProt
OPTN	NM_001008212.2	MANE Select	c.553-5C>T	splice_region intron	N/A	NP_001008213.1	Q96CV9-1
OPTN	NM_001008211.1		c.553-5C>T	splice_region intron	N/A	NP_001008212.1	Q96CV9-1
OPTN	NM_001008213.1		c.553-5C>T	splice_region intron	N/A	NP_001008214.1	Q96CV9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
OPTN	ENST00000378747.8	TSL:1 MANE Select	c.553-5C>T	splice_region intron	N/A	ENSP00000368021.3	Q96CV9-1
OPTN	ENST00000378748.7	TSL:1	c.553-5C>T	splice_region intron	N/A	ENSP00000368022.3	Q96CV9-1
OPTN	ENST00000378757.6	TSL:1	c.553-5C>T	splice_region intron	N/A	ENSP00000368032.2	Q96CV9-1

Frequencies

GnomAD3 genomes

AF:

0.809

AC:

122848

AN:

151910

Hom.:

49876

Cov.:

show subpopulations

Gnomad AFR

AF:

0.810

Gnomad AMI

AF:

0.766

Gnomad AMR

AF:

0.866

Gnomad ASJ

AF:

0.908

Gnomad EAS

AF:

0.741

Gnomad SAS

AF:

0.808

Gnomad FIN

AF:

0.709

Gnomad MID

AF:

0.943

Gnomad NFE

AF:

0.810

Gnomad OTH

AF:

0.849

GnomAD2 exomes

AF:

0.817

AC:

205038

AN:

251040

AF XY:

0.817

show subpopulations

Gnomad AFR exome

AF:

0.805

Gnomad AMR exome

AF:

0.880

Gnomad ASJ exome

AF:

0.917

Gnomad EAS exome

AF:

0.742

Gnomad FIN exome

AF:

0.716

Gnomad NFE exome

AF:

0.818

Gnomad OTH exome

AF:

0.843

GnomAD4 exome

AF:

0.806

AC:

1160698

AN:

1439214

Hom.:

469249

Cov.:

AF XY:

0.808

AC XY:

579451

AN XY:

717342

show subpopulations

African (AFR)

AF:

0.803

AC:

26478

AN:

32964

American (AMR)

AF:

0.879

AC:

39276

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.912

AC:

23703

AN:

25996

East Asian (EAS)

AF:

0.726

AC:

28704

AN:

39558

South Asian (SAS)

AF:

0.827

AC:

70930

AN:

85778

European-Finnish (FIN)

AF:

0.722

AC:

38519

AN:

53358

Middle Eastern (MID)

AF:

0.942

AC:

5408

AN:

5740

European-Non Finnish (NFE)

AF:

0.805

AC:

878578

AN:

1091494

Other (OTH)

AF:

0.823

AC:

49102

AN:

59630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

10327

20655

30982

41310

51637

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20278

40556

60834

81112

101390

<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:

0.809

AC:

122954

AN:

152028

Hom.:

49925

Cov.:

AF XY:

0.805

AC XY:

59809

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.810

AC:

33582

AN:

41458

American (AMR)

AF:

0.866

AC:

13230

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.908

AC:

3152

AN:

3472

East Asian (EAS)

AF:

0.741

AC:

3815

AN:

5148

South Asian (SAS)

AF:

0.807

AC:

3883

AN:

4812

European-Finnish (FIN)

AF:

0.709

AC:

7483

AN:

10554

Middle Eastern (MID)

AF:

0.942

AC:

277

AN:

294

European-Non Finnish (NFE)

AF:

0.809

AC:

55037

AN:

67990

Other (OTH)

AF:

0.850

AC:

1796

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1200

2399

3599

4798

5998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

880

1760

2640

3520

4400

<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:

0.820

Hom.:

231106

Bravo

AF:

0.823

Asia WGS

AF:

0.795

AC:

2766

AN:

3478

EpiCase

AF:

0.831

EpiControl

AF:

0.831

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)

Primary open angle glaucoma (2)

Amyotrophic lateral sclerosis type 12 (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

-0.85

CADD

Benign

6.8

(source)

DANN

Benign

0.53

PhyloP100

-0.12

PromoterAI

0.032

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000023

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.020

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