6-64912570-A-G

Variant names:

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.2555T>C(p.Leu852Pro) variant causes a missense change. The variant allele was found at a frequency of 0.593 in 1,550,694 control chromosomes in the GnomAD database, including 276,892 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L852A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.66 ( 34884 hom., cov: 32)

Exomes 𝑓: 0.59 ( 242008 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.23

Publications

39 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:

ENSG00000308351 (HGNC:):

ENSG00000308351 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=3.853312E-6).

BP6

Variant 6-64912570-A-G is Benign according to our data. Variant chr6-64912570-A-G is described in ClinVar as Benign. ClinVar VariationId is 93605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.2555T>C	p.Leu852Pro	missense_variant	Exon 16 of 43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2 link	c.2555T>C	p.Leu852Pro	missense_variant	Exon 16 of 44		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
EYS	ENST00000503581.6 link	c.2555T>C	p.Leu852Pro	missense_variant	Exon 16 of 43	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7 link	c.2555T>C	p.Leu852Pro	missense_variant	Exon 16 of 44	1		ENSP00000359655.3
ENSG00000308351	ENST00000833459.1 link	n.173-3753A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.664

AC:

100789

AN:

151842

Hom.:

34846

Cov.:

show subpopulations

Gnomad AFR

AF:

0.871

Gnomad AMI

AF:

0.557

Gnomad AMR

AF:

0.641

Gnomad ASJ

AF:

0.699

Gnomad EAS

AF:

0.408

Gnomad SAS

AF:

0.555

Gnomad FIN

AF:

0.577

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.583

Gnomad OTH

AF:

0.654

GnomAD2 exomes

AF:

0.593

AC:

92797

AN:

156496

AF XY:

0.586

show subpopulations

Gnomad AFR exome

AF:

0.882

Gnomad AMR exome

AF:

0.619

Gnomad ASJ exome

AF:

0.695

Gnomad EAS exome

AF:

0.402

Gnomad FIN exome

AF:

0.580

Gnomad NFE exome

AF:

0.580

Gnomad OTH exome

AF:

0.612

GnomAD4 exome

AF:

0.585

AC:

818369

AN:

1398734

Hom.:

242008

Cov.:

AF XY:

0.583

AC XY:

402451

AN XY:

689884

show subpopulations

African (AFR)

AF:

0.887

AC:

28006

AN:

31578

American (AMR)

AF:

0.626

AC:

22335

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.693

AC:

17452

AN:

25170

East Asian (EAS)

AF:

0.437

AC:

15592

AN:

35718

South Asian (SAS)

AF:

0.562

AC:

44528

AN:

79208

European-Finnish (FIN)

AF:

0.579

AC:

28540

AN:

49276

Middle Eastern (MID)

AF:

0.647

AC:

3689

AN:

5698

European-Non Finnish (NFE)

AF:

0.578

AC:

623169

AN:

1078404

Other (OTH)

AF:

0.605

AC:

35058

AN:

57978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

18110

36220

54329

72439

90549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17474

34948

52422

69896

87370

<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:

0.664

AC:

100881

AN:

151960

Hom.:

34884

Cov.:

AF XY:

0.660

AC XY:

49037

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.871

AC:

36149

AN:

41484

American (AMR)

AF:

0.641

AC:

9769

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.699

AC:

2426

AN:

3472

East Asian (EAS)

AF:

0.408

AC:

2107

AN:

5170

South Asian (SAS)

AF:

0.554

AC:

2665

AN:

4810

European-Finnish (FIN)

AF:

0.577

AC:

6094

AN:

10568

Middle Eastern (MID)

AF:

0.609

AC:

179

AN:

294

European-Non Finnish (NFE)

AF:

0.583

AC:

39600

AN:

67896

Other (OTH)

AF:

0.655

AC:

1384

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1616

3231

4847

6462

8078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

788

1576

2364

3152

3940

<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:

0.612

Hom.:

82135

Bravo

AF:

0.675

TwinsUK

AF:

0.586

AC:

2172

ALSPAC

AF:

0.568

AC:

2189

ESP6500AA

AF:

0.878

AC:

1215

ESP6500EA

AF:

0.575

AC:

1831

ExAC

AF:

0.595

AC:

14197

Asia WGS

AF:

0.556

AC:

1934

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 04, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:3

Sep 19, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 05, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is found in ARRP panel(s).

Retinitis pigmentosa

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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.

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

0.042

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.080

DEOGEN2

Benign

0.0

.;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.14

T;T

MetaRNN

Benign

0.0000039

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.56

N;N

PhyloP100

4.2

PrimateAI

Benign

0.26

PROVEAN

Benign

4.3

N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Vest4

0.059

ClinPred

0.0061

GERP RS

3.1

Varity_R

0.047

gMVP

0.93

Mutation Taster

=90/10

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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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