NM_001008212.2:c.-215G>A

Variant names:

• chr10-13100251-G-A
• rs11548142
• NM_001008212.2:c.-215G>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.-215G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,900 control chromosomes in the GnomAD database, including 3,544 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3521 hom., cov: 34)
  • Exomes 𝑓: 0.21 (23 hom.)
• Consequence: OPTN NM_001008212.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.169
• Publications: 10 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=-0.72).
• BP6: Variant 10-13100251-G-A is Benign according to our data. Variant chr10-13100251-G-A is described in ClinVar as Benign. ClinVar VariationId is 299207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.26 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.-215G>A		5_prime_UTR	Exon 1 of 15	NP_001008213.1	Q96CV9-1
	OPTN	NM_001008211.1		c.-284G>A		5_prime_UTR	Exon 1 of 16	NP_001008212.1	Q96CV9-1
	OPTN	NM_001008213.1		c.-269G>A		5_prime_UTR	Exon 1 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.-215G>A		5_prime_UTR	Exon 1 of 15	ENSP00000368021.3	Q96CV9-1
	OPTN	ENST00000378748.7	TSL:1	c.-284G>A		5_prime_UTR	Exon 1 of 16	ENSP00000368022.3	Q96CV9-1
	OPTN	ENST00000378757.6	TSL:1	c.-63G>A		5_prime_UTR	Exon 1 of 14	ENSP00000368032.2	Q96CV9-1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29731 AN: 152076 Hom.: 3518 Cov.: 34

Gnomad AFR AF: 0.0523

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.224

GnomAD4 exome AF: 0.205 AC: 147 AN: 716 Hom.: 23 Cov.: 0 AF XY: 0.221 AC XY: 101 AN XY: 456

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.100 AC: 1 AN: 10

South Asian (SAS) AF: 0.170 AC: 59 AN: 348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AF: 0.750 AC: 3 AN: 4

European-Non Finnish (NFE) AF: 0.236 AC: 77 AN: 326

Other (OTH) AF: 0.500 AC: 6 AN: 12

GnomAD4 genome AF: 0.195 AC: 29729 AN: 152184 Hom.: 3521 Cov.: 34 AF XY: 0.195 AC XY: 14482 AN XY: 74398

African (AFR) AF: 0.0521 AC: 2164 AN: 41566

American (AMR) AF: 0.249 AC: 3813 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1078 AN: 3472

East Asian (EAS) AF: 0.176 AC: 903 AN: 5144

South Asian (SAS) AF: 0.238 AC: 1149 AN: 4828

European-Finnish (FIN) AF: 0.187 AC: 1987 AN: 10604

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.263 AC: 17894 AN: 67956

Other (OTH) AF: 0.226 AC: 479 AN: 2116

Alfa AF: 0.218 Hom.: 1229

Bravo AF: 0.194

Asia WGS AF: 0.191 AC: 660 AN: 3460

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Amyotrophic lateral sclerosis type 12 (1)
-	-	1	not provided (1)
-	-	1	Primary open angle glaucoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		-0.17
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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: rs11548142; hg19: chr10-13142251;