rs113955718

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001008212.2(OPTN):c.402C>A(p.Ala134=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,898 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 18 hom., cov: 31)

Exomes 𝑓: 0.00077 ( 12 hom. )

Consequence

OPTN
NM_001008212.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.229

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 10-13112485-C-A is Benign according to our data. Variant chr10-13112485-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 299210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-13112485-C-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.229 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00728 (1107/152016) while in subpopulation AFR AF= 0.0252 (1046/41438). AF 95% confidence interval is 0.024. There are 18 homozygotes in gnomad4. There are 513 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
OPTN	NM_001008212.2 linkuse as main transcript	c.402C>A	p.Ala134=	synonymous_variant	5/15	ENST00000378747.8	NP_001008213.1
OPTN	NM_001008211.1 linkuse as main transcript	c.402C>A	p.Ala134=	synonymous_variant	6/16		NP_001008212.1
OPTN	NM_001008213.1 linkuse as main transcript	c.402C>A	p.Ala134=	synonymous_variant	6/16		NP_001008214.1
OPTN	NM_021980.4 linkuse as main transcript	c.402C>A	p.Ala134=	synonymous_variant	4/14		NP_068815.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPTN	ENST00000378747.8 linkuse as main transcript	c.402C>A	p.Ala134=	synonymous_variant	5/15	1	NM_001008212.2	ENSP00000368021	P3	Q96CV9-1

Frequencies

GnomAD3 genomes

AF:

0.00725

AC:

1102

AN:

151898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0252

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00256

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00196

AC:

492

AN:

251438

Hom.:

AF XY:

0.00141

AC XY:

191

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0254

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000768

AC:

1123

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000635

AC XY:

462

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0252

Gnomad4 AMR exome

AF:

0.00179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000412

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.00199

GnomAD4 genome

AF:

0.00728

AC:

1107

AN:

152016

Hom.:

Cov.:

AF XY:

0.00690

AC XY:

513

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0252

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00664

Alfa

AF:

0.00325

Hom.:

Bravo

AF:

0.00818

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 21, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Amyotrophic lateral sclerosis type 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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 27, 2024

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 15, 2021

- -

Primary open angle glaucoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.48

DANN

Benign

0.31

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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