rs66462731

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001142800.2(EYS):c.7666A>T(p.Ser2556Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0832 in 1,548,568 control chromosomes in the GnomAD database, including 5,872 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2556G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.081 ( 563 hom., cov: 32)

Exomes 𝑓: 0.083 ( 5309 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.47

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002138704).

BP6

Variant 6-63788162-T-A is Benign according to our data. Variant chr6-63788162-T-A is described in ClinVar as [Benign]. Clinvar id is 137259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-63788162-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2 linkuse as main transcript	c.7666A>T	p.Ser2556Cys	missense_variant	39/43	ENST00000503581.6
EYS	NM_001292009.2 linkuse as main transcript	c.7666A>T	p.Ser2556Cys	missense_variant	39/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6 linkuse as main transcript	c.7666A>T	p.Ser2556Cys	missense_variant	39/43	5	NM_001142800.2	A2	Q5T1H1-1
EYS	ENST00000370621.7 linkuse as main transcript	c.7666A>T	p.Ser2556Cys	missense_variant	39/44	1		P2	Q5T1H1-3
EYS	ENST00000398580.3 linkuse as main transcript	c.982A>T	p.Ser328Cys	missense_variant	7/10	5
EYS	ENST00000486069.1 linkuse as main transcript	n.306A>T		non_coding_transcript_exon_variant	3/6	3

Frequencies

GnomAD3 genomes

AF:

0.0812

AC:

12352

AN:

152084

Hom.:

561

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0599

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.0956

Gnomad ASJ

AF:

0.0579

Gnomad EAS

AF:

0.163

Gnomad SAS

AF:

0.0667

Gnomad FIN

AF:

0.122

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0811

Gnomad OTH

AF:

0.0626

GnomAD3 exomes

AF:

0.0942

AC:

14527

AN:

154166

Hom.:

789

AF XY:

0.0911

AC XY:

7436

AN XY:

81638

show subpopulations

Gnomad AFR exome

AF:

0.0586

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.0605

Gnomad EAS exome

AF:

0.167

Gnomad SAS exome

AF:

0.0682

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.0783

Gnomad OTH exome

AF:

0.0802

GnomAD4 exome

AF:

0.0834

AC:

116412

AN:

1396366

Hom.:

5309

Cov.:

AF XY:

0.0832

AC XY:

57280

AN XY:

688648

show subpopulations

Gnomad4 AFR exome

AF:

0.0617

Gnomad4 AMR exome

AF:

0.128

Gnomad4 ASJ exome

AF:

0.0589

Gnomad4 EAS exome

AF:

0.193

Gnomad4 SAS exome

AF:

0.0694

Gnomad4 FIN exome

AF:

0.115

Gnomad4 NFE exome

AF:

0.0797

Gnomad4 OTH exome

AF:

0.0753

GnomAD4 genome

AF:

0.0812

AC:

12366

AN:

152202

Hom.:

563

Cov.:

AF XY:

0.0833

AC XY:

6199

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0599

Gnomad4 AMR

AF:

0.0961

Gnomad4 ASJ

AF:

0.0579

Gnomad4 EAS

AF:

0.164

Gnomad4 SAS

AF:

0.0667

Gnomad4 FIN

AF:

0.122

Gnomad4 NFE

AF:

0.0811

Gnomad4 OTH

AF:

0.0610

Alfa

AF:

0.0717

Hom.:

336

Bravo

AF:

0.0807

TwinsUK

AF:

0.0785

AC:

291

ALSPAC

AF:

0.0846

AC:

326

ESP6500AA

AF:

0.0600

AC:

ESP6500EA

AF:

0.0842

AC:

268

ExAC

AF:

0.0725

AC:

1715

Asia WGS

AF:

0.0930

AC:

326

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2014	- -

Retinitis pigmentosa

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Retinitis pigmentosa 25

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.22

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Benign

0.10

Eigen_PC

Benign

0.063

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.75

T;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.33

PROVEAN

Benign

0.020

N;N

REVEL

Uncertain

0.41

Sift

Benign

0.080

T;T

Sift4G

Uncertain

0.043

D;D

Polyphen

0.99

D;D

Vest4

0.28

MPC

0.043

ClinPred

0.024

GERP RS

2.9

Varity_R

0.059

gMVP

0.56

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