NM_001008212.2:c.123G>A

Variant names:

• chr10-13109245-G-A
• rs11591687
• NM_001008212.2:c.123G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001008212.2(OPTN):​c.123G>A​(p.Leu41Leu) 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:9
• Conservation: PhyloP100: 1.03
• Publications: 13 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 -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 Benign/Likely_benign. ClinVar VariationId is 96023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD,SD gene

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.123G>A	p.Leu41Leu	synonymous	Exon 3 of 15	NP_001008213.1	Q96CV9-1
	OPTN	NM_001008211.1		c.123G>A	p.Leu41Leu	synonymous	Exon 4 of 16	NP_001008212.1	Q96CV9-1
	OPTN	NM_001008213.1		c.123G>A	p.Leu41Leu	synonymous	Exon 4 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.123G>A	p.Leu41Leu	synonymous	Exon 3 of 15	ENSP00000368021.3	Q96CV9-1
	OPTN	ENST00000378748.7	TSL:1	c.123G>A	p.Leu41Leu	synonymous	Exon 4 of 16	ENSP00000368022.3	Q96CV9-1
	OPTN	ENST00000378757.6	TSL:1	c.123G>A	p.Leu41Leu	synonymous	Exon 2 of 14	ENSP00000368032.2	Q96CV9-1

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

GnomAD2 exomes AF: 0.00719 AC: 1807 AN: 251220 AF XY: 0.00702

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 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

African (AFR) AF: 0.00155 AC: 52 AN: 33480

American (AMR) AF: 0.00277 AC: 124 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.00165 AC: 142 AN: 86258

European-Finnish (FIN) AF: 0.0126 AC: 671 AN: 53364

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0121 AC: 13462 AN: 1111880

Other (OTH) AF: 0.00926 AC: 559 AN: 60382

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

African (AFR) AF: 0.00188 AC: 78 AN: 41558

American (AMR) AF: 0.00183 AC: 28 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5162

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4812

European-Finnish (FIN) AF: 0.0130 AC: 138 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0118 AC: 804 AN: 68004

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00913 Hom.: 8

Bravo AF: 0.00652

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.00836

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Amyotrophic lateral sclerosis type 12 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Primary open angle glaucoma (1)
-	-	1	Primary open angle glaucoma;C1842026:Glaucoma 1, open angle, E;C3150692:Amyotrophic lateral sclerosis type 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.4
DANN	Benign	0.73
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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