rs66462731

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 12/21 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. S2556N) 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

Publications

24 publications found

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 Gene-Disease associations (from GenCC):

EYS-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
retinitis pigmentosa 25
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

EYS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.7666A>T	p.Ser2556Cys	missense_variant	Exon 39 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 link	c.7666A>T	p.Ser2556Cys	missense_variant	Exon 39 of 44		NP_001278938.1	Q5T1H1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EYS	ENST00000503581.6 link	c.7666A>T	p.Ser2556Cys	missense_variant	Exon 39 of 43	5	NM_001142800.2	ENSP00000424243.1	Q5T1H1-1
EYS	ENST00000370621.7 link	c.7666A>T	p.Ser2556Cys	missense_variant	Exon 39 of 44	1		ENSP00000359655.3	Q5T1H1-3
EYS	ENST00000398580.3 link	c.979A>T	p.Ser327Cys	missense_variant	Exon 7 of 10	5		ENSP00000381585.3	H0Y3Q4
EYS	ENST00000486069.1 link	n.306A>T		non_coding_transcript_exon_variant	Exon 3 of 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

GnomAD2 exomes

AF:

0.0942

AC:

14527

AN:

154166

AF XY:

0.0911

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 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

African (AFR)

AF:

0.0617

AC:

1945

AN:

31502

American (AMR)

AF:

0.128

AC:

4504

AN:

35268

Ashkenazi Jewish (ASJ)

AF:

0.0589

AC:

1481

AN:

25142

East Asian (EAS)

AF:

0.193

AC:

6877

AN:

35622

South Asian (SAS)

AF:

0.0694

AC:

5444

AN:

78392

European-Finnish (FIN)

AF:

0.115

AC:

5664

AN:

49264

Middle Eastern (MID)

AF:

0.0437

AC:

249

AN:

5694

European-Non Finnish (NFE)

AF:

0.0797

AC:

85890

AN:

1077578

Other (OTH)

AF:

0.0753

AC:

4358

AN:

57904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

4965

9930

14896

19861

24826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0812

AC:

12366

AN:

152202

Hom.:

563

Cov.:

AF XY:

0.0833

AC XY:

6199

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0599

AC:

2486

AN:

41534

American (AMR)

AF:

0.0961

AC:

1469

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0579

AC:

201

AN:

3470

East Asian (EAS)

AF:

0.164

AC:

851

AN:

5182

South Asian (SAS)

AF:

0.0667

AC:

322

AN:

4824

European-Finnish (FIN)

AF:

0.122

AC:

1291

AN:

10586

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0811

AC:

5517

AN:

68002

Other (OTH)

AF:

0.0610

AC:

129

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

577

1154

1730

2307

2884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Jul 13, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 19, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 25

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

.;T

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

PhyloP100

2.5

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

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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rs66462731

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