rs778030177

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001142800.2(EYS):c.1765A>G(p.Arg589Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000423 in 1,606,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

EYS
NM_001142800.2 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 2.65

Variant links:

Genes affected

EYS (HGNC:21555): (eyes shut homolog) The product of this gene contains multiple epidermal growth factor (EGF)-like and LamG domains. The protein is expressed in the photoreceptor layer of the retina, and the gene is mutated in autosomal recessive retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

EYS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-65334981-T-C is Pathogenic according to our data. Variant chr6-65334981-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-65334981-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.1765A>G	p.Arg589Gly	missense_variant, splice_region_variant	Exon 11 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_198283.2 link	c.1765A>G	p.Arg589Gly	missense_variant	Exon 10 of 10		NP_938024.1	Q5T1H1-2
EYS	NM_001292009.2 link	c.1765A>G	p.Arg589Gly	missense_variant, splice_region_variant	Exon 11 of 44		NP_001278938.1	Q5T1H1-3
EYS	NM_001142801.2 link	c.1765A>G	p.Arg589Gly	missense_variant, splice_region_variant	Exon 11 of 12		NP_001136273.1	Q5T1H1-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EYS	ENST00000342421.9 link	c.1765A>G	p.Arg589Gly	missense_variant	Exon 9 of 9	1		ENSP00000341818.5	Q5T1H1-2
EYS	ENST00000503581.6 link	c.1765A>G	p.Arg589Gly	missense_variant, splice_region_variant	Exon 11 of 43	5	NM_001142800.2	ENSP00000424243.1	Q5T1H1-1
EYS	ENST00000370621.7 link	c.1765A>G	p.Arg589Gly	missense_variant, splice_region_variant	Exon 11 of 44	1		ENSP00000359655.3	Q5T1H1-3
EYS	ENST00000393380.6 link	c.1765A>G	p.Arg589Gly	missense_variant, splice_region_variant	Exon 11 of 12	1		ENSP00000377042.2	Q5T1H1-4

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000962

AC:

AN:

249410

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

134884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000797

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000419

AC:

AN:

1454324

Hom.:

Cov.:

AF XY:

0.0000497

AC XY:

AN XY:

723918

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.000247

Gnomad4 ASJ exome

AF:

0.000423

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000289

Gnomad4 OTH exome

AF:

0.0000832

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151772

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74116

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000756

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Pathogenic:2Uncertain:2

May 07, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2017

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Jan 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macular dystrophy

Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Pathogenic:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 589 of the EYS protein (p.Arg589Gly). This variant is present in population databases (rs778030177, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of retinitis pigmentosa (PMID: 20237254, 30153090; internal data). ClinVar contains an entry for this variant (Variation ID: 551672). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.033

.;T;.;.

Eigen

Benign

0.032

Eigen_PC

Benign

0.039

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.51

T;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.43

T;T;T;T

MetaSVM

Benign

-0.29

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.3

N;N;N;N

REVEL

Uncertain

0.45

Sift

Benign

0.11

T;T;D;T

Sift4G

Uncertain

0.0020

D;D;T;T

Polyphen

0.96

D;.;.;D

Vest4

0.51

MVP

0.49

MPC

0.010

ClinPred

0.46

GERP RS

3.4

Varity_R

0.17

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.30

Position offset: -1

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