NM_001142800.2:c.5244A>C

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.5244A>C(p.Leu1748Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,551,050 control chromosomes in the GnomAD database, including 12,752 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 (★★).

Frequency

Genomes: 𝑓 0.10 ( 921 hom., cov: 33)

Exomes 𝑓: 0.13 ( 11831 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.162

Publications

14 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=0.0030450225).

BP6

Variant 6-64590623-T-G is Benign according to our data. Variant chr6-64590623-T-G is described in ClinVar as [Benign]. Clinvar id is 93616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.5244A>C	p.Leu1748Phe	missense_variant	Exon 26 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 link	c.5244A>C	p.Leu1748Phe	missense_variant	Exon 26 of 44		NP_001278938.1	Q5T1H1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6 link	c.5244A>C	p.Leu1748Phe	missense_variant	Exon 26 of 43	5	NM_001142800.2	ENSP00000424243.1		Q5T1H1-1
EYS	ENST00000370621.7 link	c.5244A>C	p.Leu1748Phe	missense_variant	Exon 26 of 44	1		ENSP00000359655.3		Q5T1H1-3

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15866

AN:

152094

Hom.:

922

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0665

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0607

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.0203

Gnomad SAS

AF:

0.0909

Gnomad FIN

AF:

0.181

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.0861

GnomAD2 exomes

AF:

0.102

AC:

15658

AN:

153662

AF XY:

0.104

show subpopulations

Gnomad AFR exome

AF:

0.0647

Gnomad AMR exome

AF:

0.0471

Gnomad ASJ exome

AF:

0.101

Gnomad EAS exome

AF:

0.0102

Gnomad FIN exome

AF:

0.175

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.104

GnomAD4 exome

AF:

0.126

AC:

175844

AN:

1398838

Hom.:

11831

Cov.:

AF XY:

0.125

AC XY:

86071

AN XY:

689922

show subpopulations

African (AFR)

AF:

0.0614

AC:

1939

AN:

31572

American (AMR)

AF:

0.0503

AC:

1795

AN:

35694

Ashkenazi Jewish (ASJ)

AF:

0.0999

AC:

2513

AN:

25152

East Asian (EAS)

AF:

0.0400

AC:

1430

AN:

35722

South Asian (SAS)

AF:

0.0961

AC:

7613

AN:

79224

European-Finnish (FIN)

AF:

0.177

AC:

8716

AN:

49256

Middle Eastern (MID)

AF:

0.0506

AC:

288

AN:

5696

European-Non Finnish (NFE)

AF:

0.135

AC:

145283

AN:

1078546

Other (OTH)

AF:

0.108

AC:

6267

AN:

57976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

8473

16946

25419

33892

42365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5196

10392

15588

20784

25980

<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:

0.104

AC:

15861

AN:

152212

Hom.:

921

Cov.:

AF XY:

0.104

AC XY:

7750

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0664

AC:

2759

AN:

41554

American (AMR)

AF:

0.0605

AC:

924

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

364

AN:

3466

East Asian (EAS)

AF:

0.0203

AC:

105

AN:

5168

South Asian (SAS)

AF:

0.0902

AC:

436

AN:

4834

European-Finnish (FIN)

AF:

0.181

AC:

1920

AN:

10612

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.134

AC:

9132

AN:

67982

Other (OTH)

AF:

0.0857

AC:

181

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

731

1461

2192

2922

3653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<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:

0.122

Hom.:

3947

Bravo

AF:

0.0929

TwinsUK

AF:

0.129

AC:

477

ALSPAC

AF:

0.141

AC:

542

ESP6500AA

AF:

0.0824

AC:

114

ESP6500EA

AF:

0.133

AC:

422

ExAC

AF:

0.0973

AC:

2065

Asia WGS

AF:

0.0540

AC:

188

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 20, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is found in ARRP panel(s). -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not specified

Benign:1

Oct 08, 2013

Eurofins Ntd Llc (ga)

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

0.18

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.54

CADD

Benign

2.4

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.098

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.34

T;T

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.55

N;N

PhyloP100

-0.16

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.28

N;N

REVEL

Benign

0.11

Sift

Benign

0.31

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.40

B;B

Vest4

0.023

MutPred

0.34

Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);

MPC

0.059

ClinPred

0.0044

GERP RS

-7.6

Varity_R

0.049

gMVP

0.0084

Mutation Taster

=88/12

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