rs11591687

chr10-13109245-G-Achr10-13109245-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001008212.2(OPTN):c.123G>A(p.Leu41=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,613,908 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (6 hom., cov: 30)
  • Exomes 𝑓: 0.010 (85 hom.)
• Consequence: OPTN NM_001008212.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.03

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 10-13109245-G-A is Benign according to our data. Variant chr10-13109245-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 96023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-13109245-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00709 (1079/152216) while in subpopulation NFE AF= 0.0118 (804/68004). AF 95% confidence interval is 0.0111. There are 6 homozygotes in gnomad4. There are 518 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPTN	NM_001008212.2	c.123G>A	p.Leu41=	synonymous_variant	3/15	ENST00000378747.8
OPTN	NM_001008211.1	c.123G>A	p.Leu41=	synonymous_variant	4/16
OPTN	NM_001008213.1	c.123G>A	p.Leu41=	synonymous_variant	4/16
OPTN	NM_021980.4	c.123G>A	p.Leu41=	synonymous_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPTN	ENST00000378747.8	c.123G>A	p.Leu41=	synonymous_variant	3/15	1	NM_001008212.2	P3

Frequencies

GnomAD3 genomes AF: 0.00709 AC: 1079 AN: 152098 Hom.: 6 Cov.: 30

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00719 AC: 1807 AN: 251220 Hom.: 11 AF XY: 0.00702 AC XY: 953 AN XY: 135792

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.0103 AC: 15064 AN: 1461692 Hom.: 85 Cov.: 33 AF XY: 0.0100 AC XY: 7287 AN XY: 727136

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00165

Gnomad4 FIN exome AF: 0.0126

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.00926

GnomAD4 genome AF: 0.00709 AC: 1079 AN: 152216 Hom.: 6 Cov.: 30 AF XY: 0.00696 AC XY: 518 AN XY: 74412

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00944 Hom.: 8

Bravo AF: 0.00652

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.00836

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	OPTN: BP4, BP7, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 10, 2013

- -

Amyotrophic lateral sclerosis type 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Invitae

Jan 29, 2024

- -

Primary open angle glaucoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	6.4
Dann	Benign	0.73
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

Other links and lift over

dbSNP: rs11591687; hg19: chr10-13151245; COSMIC: COSV53811881; COSMIC: COSV53811881;