rs1131690780

chr10-13127839-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001008212.2(OPTN):c.1337A>G(p.Glu446Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OPTN NM_001008212.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a region_of_interest Interaction with MYO6 (size 108) in uniprot entity OPTN_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001008212.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12793434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPTN	NM_001008212.2	c.1337A>G	p.Glu446Gly	missense_variant	12/15	ENST00000378747.8
OPTN	NM_001008211.1	c.1337A>G	p.Glu446Gly	missense_variant	13/16
OPTN	NM_001008213.1	c.1337A>G	p.Glu446Gly	missense_variant	13/16
OPTN	NM_021980.4	c.1337A>G	p.Glu446Gly	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPTN	ENST00000378747.8	c.1337A>G	p.Glu446Gly	missense_variant	12/15	1	NM_001008212.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Motor neuron disease Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Centre for Genomic and Experimental Medicine, University of Edinburgh

Aug 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.;D;.;D;D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.4	M;.;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.024	D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		0.013	B;B;B;B;B;B
Vest4		0.18
MutPred		0.11		Gain of MoRF binding (P = 0.0551);.;Gain of MoRF binding (P = 0.0551);.;Gain of MoRF binding (P = 0.0551);Gain of MoRF binding (P = 0.0551);
MVP		0.96
MPC		0.20
ClinPred		0.96	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.27

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: rs1131690780; hg19: chr10-13169839;