NM_001008212.2:c.46C>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001008212.2(OPTN):c.46C>G(p.Pro16Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

OPTN
NM_001008212.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.127

Publications

4 publications found

Variant links:

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: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
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

OPTN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07324728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPTN	NM_001008212.2 link	c.46C>G	p.Pro16Ala	missense_variant	Exon 3 of 15	ENST00000378747.8	NP_001008213.1	Q96CV9-1
OPTN	NM_001008211.1 link	c.46C>G	p.Pro16Ala	missense_variant	Exon 4 of 16		NP_001008212.1	Q96CV9-1
OPTN	NM_001008213.1 link	c.46C>G	p.Pro16Ala	missense_variant	Exon 4 of 16		NP_001008214.1	Q96CV9-1
OPTN	NM_021980.4 link	c.46C>G	p.Pro16Ala	missense_variant	Exon 2 of 14		NP_068815.2	Q96CV9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPTN	ENST00000378747.8 link	c.46C>G	p.Pro16Ala	missense_variant	Exon 3 of 15	1	NM_001008212.2	ENSP00000368021.3		Q96CV9-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251364

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000629

AC:

AN:

1111998

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41398

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jun 29, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P16A variant (also known as c.46C>G), located in coding exon 1 of the OPTN gene, results from a C to G substitution at nucleotide position 46. The proline at codon 16 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. This variant has been described in a single individual affected with sporadic ALS but zygosity of the alteration is unclear (Lattante S et al. Neurology, 2012 Jul;79:66-72). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

OPTN-related disorder

Uncertain:1

Oct 07, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The OPTN c.46C>G variant is predicted to result in the amino acid substitution p.Pro16Ala. This variant was reported in an individual with amyotrophic lateral sclerosis (Lattante et al 2012. PubMed ID: 22722621). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-13151168-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OPTN: PM2, BP4 -

Primary open angle glaucoma;C1842026:Glaucoma 1, open angle, E;C3150692:Amyotrophic lateral sclerosis type 12

Uncertain:1

Nov 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 22722621). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 16 of the OPTN protein (p.Pro16Ala). This variant is present in population databases (rs758942502, gnomAD 0.003%). ClinVar contains an entry for this variant (Variation ID: 447911). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

8.9

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.14

T;.;T;.;T;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.68

.;.;.;T;.;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.073

T;T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.7

L;L;L;L;L;L

PhyloP100

0.13

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.66

N;N;N;N;N;N

REVEL

Uncertain

0.47

Sift

Benign

0.11

T;T;T;T;T;T

Sift4G

Benign

0.96

T;T;T;T;T;T

Polyphen

0.0050

B;B;B;B;B;B

Vest4

0.23

MutPred

0.12

Loss of glycosylation at P16 (P = 0.0572);Loss of glycosylation at P16 (P = 0.0572);Loss of glycosylation at P16 (P = 0.0572);Loss of glycosylation at P16 (P = 0.0572);Loss of glycosylation at P16 (P = 0.0572);Loss of glycosylation at P16 (P = 0.0572);

MVP

0.89

MPC

0.26

ClinPred

0.019

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.024

gMVP

0.45

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over