rs11258194

Variant names:

• chr10-13110400-T-A
• rs11258194
• NM_001008212.2:c.293T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 16/21 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:15 O:1
• Conservation: PhyloP100: 0.0630
• Publications: 126 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 7099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPTN	NM_001008212.2	MANE Select	c.293T>A	p.Met98Lys	missense	Exon 4 of 15	NP_001008213.1	Q96CV9-1
	OPTN	NM_001008211.1		c.293T>A	p.Met98Lys	missense	Exon 5 of 16	NP_001008212.1	Q96CV9-1
	OPTN	NM_001008213.1		c.293T>A	p.Met98Lys	missense	Exon 5 of 16	NP_001008214.1	Q96CV9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPTN	ENST00000378747.8	TSL:1 MANE Select	c.293T>A	p.Met98Lys	missense	Exon 4 of 15	ENSP00000368021.3	Q96CV9-1
	OPTN	ENST00000378748.7	TSL:1	c.293T>A	p.Met98Lys	missense	Exon 5 of 16	ENSP00000368022.3	Q96CV9-1
	OPTN	ENST00000378757.6	TSL:1	c.293T>A	p.Met98Lys	missense	Exon 3 of 14	ENSP00000368032.2	Q96CV9-1

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

GnomAD2 exomes AF: 0.0442 AC: 11112 AN: 251306 AF XY: 0.0430

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 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

African (AFR) AF: 0.121 AC: 4065 AN: 33480

American (AMR) AF: 0.0211 AC: 942 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0711 AC: 1859 AN: 26134

East Asian (EAS) AF: 0.0983 AC: 3903 AN: 39698

South Asian (SAS) AF: 0.0491 AC: 4239 AN: 86252

European-Finnish (FIN) AF: 0.0251 AC: 1339 AN: 53402

Middle Eastern (MID) AF: 0.0600 AC: 346 AN: 5768

European-Non Finnish (NFE) AF: 0.0281 AC: 31226 AN: 1111960

Other (OTH) AF: 0.0485 AC: 2927 AN: 60388

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

African (AFR) AF: 0.119 AC: 4950 AN: 41502

American (AMR) AF: 0.0298 AC: 455 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0711 AC: 247 AN: 3472

East Asian (EAS) AF: 0.135 AC: 697 AN: 5168

South Asian (SAS) AF: 0.0516 AC: 249 AN: 4828

European-Finnish (FIN) AF: 0.0289 AC: 306 AN: 10606

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0280 AC: 1906 AN: 68030

Other (OTH) AF: 0.0567 AC: 120 AN: 2116

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Primary open angle glaucoma (2)
-	-	1	Amyotrophic lateral sclerosis type 12 (1)
1	-	-	Glaucoma 1, open angle, E (1)
-	-	1	Primary open angle glaucoma;C1842026:Glaucoma 1, open angle, E;C3150692:Amyotrophic lateral sclerosis type 12 (1)
-	-	1	Primary open angle glaucoma;C1847730:Glaucoma, normal tension, susceptibility to;C3150692:Amyotrophic lateral sclerosis type 12 (1)
-	-	1	Primary open angle glaucoma;C3150692:Amyotrophic lateral sclerosis type 12 (1)
-	-	-	Glaucoma, normal tension, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.063
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.22
Sift	Benign	0.93	T
Sift4G	Benign	0.90	T
Polyphen		0.0010	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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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