rs12415716

Variant names:

• chr10-13138287-T-G
• rs12415716
• NM_001008212.2:c.*1421T>G

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.*1421T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 178,626 control chromosomes in the GnomAD database, including 5,391 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4496 hom., cov: 33)
  • Exomes 𝑓: 0.25 (895 hom.)
• Consequence: OPTN NM_001008212.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.339
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-13138287-T-G is Benign according to our data. Variant chr10-13138287-T-G is described in ClinVar as Benign. ClinVar VariationId is 368895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.285 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.*1421T>G		3_prime_UTR	Exon 15 of 15	NP_001008213.1	Q96CV9-1
	OPTN	NM_001008211.1		c.*1421T>G		downstream_gene	N/A	NP_001008212.1	Q96CV9-1
	OPTN	NM_001008213.1		c.*1421T>G		downstream_gene	N/A	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.*1421T>G		3_prime_UTR	Exon 15 of 15	ENSP00000368021.3	Q96CV9-1
	OPTN	ENST00000378748.7	TSL:1	c.*1421T>G		3_prime_UTR	Exon 16 of 16	ENSP00000368022.3	Q96CV9-1
	OPTN	ENST00000378757.6	TSL:1	c.*1421T>G		3_prime_UTR	Exon 14 of 14	ENSP00000368032.2	Q96CV9-1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34970 AN: 152074 Hom.: 4502 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.0980

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.267

GnomAD4 exome AF: 0.248 AC: 6554 AN: 26434 Hom.: 895 Cov.: 0 AF XY: 0.250 AC XY: 3030 AN XY: 12110

African (AFR) AF: 0.148 AC: 130 AN: 880

American (AMR) AF: 0.251 AC: 142 AN: 566

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 558 AN: 1700

East Asian (EAS) AF: 0.0882 AC: 488 AN: 5532

South Asian (SAS) AF: 0.273 AC: 59 AN: 216

European-Finnish (FIN) AF: 0.125 AC: 2 AN: 16

Middle Eastern (MID) AF: 0.398 AC: 70 AN: 176

European-Non Finnish (NFE) AF: 0.298 AC: 4537 AN: 15224

Other (OTH) AF: 0.267 AC: 568 AN: 2124

GnomAD4 genome AF: 0.230 AC: 34969 AN: 152192 Hom.: 4496 Cov.: 33 AF XY: 0.225 AC XY: 16727 AN XY: 74386

African (AFR) AF: 0.137 AC: 5671 AN: 41538

American (AMR) AF: 0.262 AC: 4004 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1214 AN: 3472

East Asian (EAS) AF: 0.0984 AC: 511 AN: 5194

South Asian (SAS) AF: 0.219 AC: 1058 AN: 4824

European-Finnish (FIN) AF: 0.181 AC: 1919 AN: 10600

Middle Eastern (MID) AF: 0.387 AC: 113 AN: 292

European-Non Finnish (NFE) AF: 0.289 AC: 19632 AN: 67966

Other (OTH) AF: 0.267 AC: 563 AN: 2112

Alfa AF: 0.227 Hom.: 684

Bravo AF: 0.232

Asia WGS AF: 0.197 AC: 686 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Amyotrophic Lateral Sclerosis, Recessive (1)
-	-	1	Primary open angle glaucoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.0
DANN	Benign	0.79
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12415716; hg19: chr10-13180287;