rs2234968

chr10-13109224-G-Achr10-13109224-G-Cchr10-13109224-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001008212.2(OPTN):c.102G>A(p.Thr34=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.19

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=-0.79).
• BP6: Variant 10-13109224-G-A is Benign according to our data. Variant chr10-13109224-G-A is described in ClinVar as [Benign]. Clinvar id is 96022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-13109224-G-A is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPTN	NM_001008212.2	c.102G>A	p.Thr34=	synonymous_variant	3/15	ENST00000378747.8
OPTN	NM_001008211.1	c.102G>A	p.Thr34=	synonymous_variant	4/16
OPTN	NM_001008213.1	c.102G>A	p.Thr34=	synonymous_variant	4/16
OPTN	NM_021980.4	c.102G>A	p.Thr34=	synonymous_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPTN	ENST00000378747.8	c.102G>A	p.Thr34=	synonymous_variant	3/15	1	NM_001008212.2	P3

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30209 AN: 151882 Hom.: 3651 Cov.: 30

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

GnomAD3 exomes AF: 0.242 AC: 60876 AN: 251260 Hom.: 7960 AF XY: 0.244 AC XY: 33116 AN XY: 135822

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 SAS exome AF: 0.221

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.: 34 AF XY: 0.256 AC XY: 186429 AN XY: 727108

Gnomad4 AFR exome AF: 0.0443

Gnomad4 AMR exome AF: 0.278

Gnomad4 ASJ exome AF: 0.329

Gnomad4 EAS exome AF: 0.187

Gnomad4 SAS exome AF: 0.221

Gnomad4 FIN exome AF: 0.187

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.199 AC: 30209 AN: 152000 Hom.: 3653 Cov.: 30 AF XY: 0.197 AC XY: 14651 AN XY: 74278

Gnomad4 AFR AF: 0.0533

Gnomad4 AMR AF: 0.255

Gnomad4 ASJ AF: 0.320

Gnomad4 EAS AF: 0.187

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.182

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.237

Alfa AF: 0.258 Hom.: 10767

Bravo AF: 0.199

Asia WGS AF: 0.210 AC: 731 AN: 3478

EpiCase AF: 0.284

EpiControl AF: 0.283

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 10, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 21, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Amyotrophic lateral sclerosis type 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 19172505, 17122126, 28993189, 31198474, 17361544) -

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

Feb 01, 2024

- -

Primary open angle glaucoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.70
Dann	Benign	0.78
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: rs2234968; hg19: chr10-13151224; COSMIC: COSV53809457; COSMIC: COSV53809457;