rs150381274

chr10-13124075-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001008212.2(OPTN):c.963C>T(p.Ser321=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000923 in 1,612,530 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (10 hom.)
• Consequence: OPTN NM_001008212.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.435

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 10-13124075-C-T is Benign according to our data. Variant chr10-13124075-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 299218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-13124075-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.435 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00485 (738/152234) while in subpopulation AFR AF= 0.0167 (692/41534). AF 95% confidence interval is 0.0156. There are 8 homozygotes in gnomad4. There are 365 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPTN	NM_001008212.2	c.963C>T	p.Ser321=	synonymous_variant	9/15	ENST00000378747.8
OPTN	NM_001008211.1	c.963C>T	p.Ser321=	synonymous_variant	10/16
OPTN	NM_001008213.1	c.963C>T	p.Ser321=	synonymous_variant	10/16
OPTN	NM_021980.4	c.963C>T	p.Ser321=	synonymous_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPTN	ENST00000378747.8	c.963C>T	p.Ser321=	synonymous_variant	9/15	1	NM_001008212.2	P3

Frequencies

GnomAD3 genomes AF: 0.00475 AC: 722 AN: 152116 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00133 AC: 332 AN: 250430 Hom.: 2 AF XY: 0.00104 AC XY: 141 AN XY: 135334

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0000657

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000514 AC: 750 AN: 1460296 Hom.: 10 Cov.: 30 AF XY: 0.000475 AC XY: 345 AN XY: 726446

Gnomad4 AFR exome AF: 0.0166

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00485 AC: 738 AN: 152234 Hom.: 8 Cov.: 33 AF XY: 0.00490 AC XY: 365 AN XY: 74434

Gnomad4 AFR AF: 0.0167

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00173 Hom.: 4

Bravo AF: 0.00562

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2020	This variant is associated with the following publications: (PMID: 19096531, 21550138, 17293779) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 05, 2018	- -

Amyotrophic lateral sclerosis type 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Primary open angle glaucoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.48
Cadd	Benign	11
Dann	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs150381274; hg19: chr10-13166075; COSMIC: COSV99537457; COSMIC: COSV99537457;