rs11258210

Positions:

• chr10-13116257-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001008212.2(OPTN):​c.553-10G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,579,346 control chromosomes in the GnomAD database, including 241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (33 hom., cov: 31)
  • Exomes 𝑓: 0.0040 (208 hom.)
• Consequence: OPTN NM_001008212.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002282
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.199

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 10-13116257-G-A is Benign according to our data. Variant chr10-13116257-G-A is described in ClinVar as [Benign]. Clinvar id is 256882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-13116257-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPTN	NM_001008212.2	c.553-10G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000378747.8	NP_001008213.1
OPTN	NM_001008211.1	c.553-10G>A		splice_polypyrimidine_tract_variant, intron_variant			NP_001008212.1
OPTN	NM_001008213.1	c.553-10G>A		splice_polypyrimidine_tract_variant, intron_variant			NP_001008214.1
OPTN	NM_021980.4	c.553-10G>A		splice_polypyrimidine_tract_variant, intron_variant			NP_068815.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPTN	ENST00000378747.8	c.553-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001008212.2	ENSP00000368021	P3

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 945 AN: 152074 Hom.: 32 Cov.: 31

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0948

Gnomad SAS AF: 0.00561

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.0101 AC: 2530 AN: 251176 Hom.: 85 AF XY: 0.00888 AC XY: 1206 AN XY: 135790

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0985

Gnomad SAS exome AF: 0.00271

Gnomad FIN exome AF: 0.00189

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00403 AC: 5746 AN: 1427154 Hom.: 208 Cov.: 24 AF XY: 0.00391 AC XY: 2788 AN XY: 712282

Gnomad4 AFR exome AF: 0.000519

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.000849

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.00261

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.000395

Gnomad4 OTH exome AF: 0.00448

GnomAD4 genome AF: 0.00622 AC: 947 AN: 152192 Hom.: 33 Cov.: 31 AF XY: 0.00753 AC XY: 560 AN XY: 74394

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.0227

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0954

Gnomad4 SAS AF: 0.00582

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00134 Hom.: 2

Bravo AF: 0.00730

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 15312511) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Amyotrophic lateral sclerosis type 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Primary open angle glaucoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00023
dbscSNV1_RF	Benign	0.052
SpliceAI score (max)		0.050		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: rs11258210; hg19: chr10-13158257; COSMIC: COSV53813487; COSMIC: COSV53813487;