10-86654839-G-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033282.4(OPN4):c.56G>T(p.Cys19Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,610,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

OPN4
NM_033282.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.05

Variant links:

Genes affected

OPN4 (HGNC:14449): (opsin 4) Opsins are members of the guanine nucleotide-binding protein (G protein)-coupled receptor superfamily. This gene encodes a photoreceptive opsin protein that is expressed within the ganglion and amacrine cell layers of the retina. In mouse, retinal ganglion cell axons expressing this gene projected to the suprachiasmatic nucleus and other brain nuclei involved in circadian photoentrainment. In mouse, this protein is coupled to a transient receptor potential (TRP) ion channel through a G protein signaling pathway and produces a physiologic light response via membrane depolarization and increased intracellular calcium. The protein functions as a sensory photopigment and may also have photoisomerase activity. Experiments with knockout mice indicate that this gene attenuates, but does not abolish, photoentrainment. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

OPN4 links:

ENSG00000289258 (HGNC:):

ENSG00000289258 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05352649).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPN4	NM_033282.4 link	c.56G>T	p.Cys19Phe	missense_variant	Exon 1 of 10	ENST00000241891.10	NP_150598.1	Q9UHM6-1
OPN4	NM_001030015.3 link	c.56G>T	p.Cys19Phe	missense_variant	Exon 1 of 11		NP_001025186.1	Q9UHM6-2
OPN4	XM_017016955.2 link	c.56G>T	p.Cys19Phe	missense_variant	Exon 1 of 10		XP_016872444.1
OPN4	XM_017016956.2 link	c.56G>T	p.Cys19Phe	missense_variant	Exon 1 of 9		XP_016872445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPN4	ENST00000241891.10 link	c.56G>T	p.Cys19Phe	missense_variant	Exon 1 of 10	1	NM_033282.4	ENSP00000241891.5		Q9UHM6-1
ENSG00000289258	ENST00000443292.2 link	c.56G>T	p.Cys19Phe	missense_variant	Exon 1 of 18	1		ENSP00000393132.2		C9JWU6

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1458138

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725522

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152008

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56G>T (p.C19F) alteration is located in exon 1 (coding exon 1) of the OPN4 gene. This alteration results from a G to T substitution at nucleotide position 56, causing the cysteine (C) at amino acid position 19 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.67

DEOGEN2

Benign

0.16

.;T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.54

T;T;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.054

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;L;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.2

N;N;N

REVEL

Benign

0.073

Sift

Benign

0.38

T;T;T

Sift4G

Benign

0.42

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.12

MutPred

0.14

Loss of glycosylation at P23 (P = 0.1225);Loss of glycosylation at P23 (P = 0.1225);Loss of glycosylation at P23 (P = 0.1225);

MVP

0.33

MPC

0.074

ClinPred

0.036

GERP RS

2.9

Varity_R

0.084

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over