rs11258194

chr10-13110400-T-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001008212.2(OPTN):c.293T>A(p.Met98Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,614,026 control chromosomes in the GnomAD database, including 1,623 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (376 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1247 hom.)
• Consequence: OPTN NM_001008212.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:13 O:1
• Conservation: PhyloP100: 0.0630

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 -18 ACMG points.

• PM1: In a helix (size 61) in uniprot entity OPTN_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001008212.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016944706).
• BP6: Variant 10-13110400-T-A is Benign according to our data. Variant chr10-13110400-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 7099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-13110400-T-A is described in Lovd as [Likely_benign]. Variant chr10-13110400-T-A is described in Lovd as [Benign]. Variant chr10-13110400-T-A is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPTN	NM_001008212.2	c.293T>A	p.Met98Lys	missense_variant	4/15	ENST00000378747.8
OPTN	NM_001008211.1	c.293T>A	p.Met98Lys	missense_variant	5/16
OPTN	NM_001008213.1	c.293T>A	p.Met98Lys	missense_variant	5/16
OPTN	NM_021980.4	c.293T>A	p.Met98Lys	missense_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPTN	ENST00000378747.8	c.293T>A	p.Met98Lys	missense_variant	4/15	1	NM_001008212.2	P3

Frequencies

GnomAD3 genomes AF: 0.0591 AC: 8982 AN: 152102 Hom.: 373 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0298

Gnomad ASJ AF: 0.0711

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0519

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0280

Gnomad OTH AF: 0.0578

GnomAD3 exomes AF: 0.0442 AC: 11112 AN: 251306 Hom.: 417 AF XY: 0.0430 AC XY: 5846 AN XY: 135850

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.0727

Gnomad EAS exome AF: 0.126

Gnomad SAS exome AF: 0.0471

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0437

GnomAD4 exome AF: 0.0348 AC: 50846 AN: 1461806 Hom.: 1247 Cov.: 33 AF XY: 0.0351 AC XY: 25532 AN XY: 727196

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.0211

Gnomad4 ASJ exome AF: 0.0711

Gnomad4 EAS exome AF: 0.0983

Gnomad4 SAS exome AF: 0.0491

Gnomad4 FIN exome AF: 0.0251

Gnomad4 NFE exome AF: 0.0281

Gnomad4 OTH exome AF: 0.0485

GnomAD4 genome AF: 0.0590 AC: 8982 AN: 152220 Hom.: 376 Cov.: 32 AF XY: 0.0593 AC XY: 4413 AN XY: 74414

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0298

Gnomad4 ASJ AF: 0.0711

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.0516

Gnomad4 FIN AF: 0.0289

Gnomad4 NFE AF: 0.0280

Gnomad4 OTH AF: 0.0567

Alfa AF: 0.0381 Hom.: 126

Bravo AF: 0.0618

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0280 AC: 108

ESP6500AA AF: 0.118 AC: 518

ESP6500EA AF: 0.0322 AC: 277

ExAC AF: 0.0449 AC: 5451

Asia WGS AF: 0.0990 AC: 345 AN: 3478

EpiCase AF: 0.0309

EpiControl AF: 0.0310

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2018	This variant is associated with the following publications: (PMID: 16358725, 17361544, 31198474, 31182772, 17293779, 28430856, 26376340, 25681989, 15226658, 11834836, 19172505, 17122126, 23357852) -

Primary open angle glaucoma Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Glaucoma 1, open angle, E Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 08, 2002

- -

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. -

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 31, 2024

- -

Primary open angle glaucoma;C1847730:Glaucoma, normal tension, susceptibility to;C3150692:Amyotrophic lateral sclerosis type 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 25, 2022

- -

Glaucoma, normal tension, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 08, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	4.8
Dann	Benign	0.64
DEOGEN2	Benign	0.14	T;.;T;.;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.047	N
MetaRNN	Benign	0.0017	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.060	N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.93	T;T;T;T;T;T
Sift4G	Benign	0.90	T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B;B
Vest4		0.081
MPC		0.27
ClinPred		0.00087	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.17

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: rs11258194; hg19: chr10-13152400; COSMIC: COSV53809711; COSMIC: COSV53809711;