chr6-64886797-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BP4

The NM_001142800.2(EYS):c.2892A>C(p.Glu964Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,546,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E964K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 0.314

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant 6-64886797-T-G is Pathogenic according to our data. Variant chr6-64886797-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 554346.

BP4

Computational evidence support a benign effect (MetaRNN=0.057252854). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142800.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	NM_001142800.2	MANE Select	c.2892A>C	p.Glu964Asp	missense	Exon 19 of 43	NP_001136272.1
	EYS	NM_001292009.2		c.2892A>C	p.Glu964Asp	missense	Exon 19 of 44	NP_001278938.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	ENST00000503581.6	TSL:5 MANE Select	c.2892A>C	p.Glu964Asp	missense	Exon 19 of 43	ENSP00000424243.1
	EYS	ENST00000370621.7	TSL:1	c.2892A>C	p.Glu964Asp	missense	Exon 19 of 44	ENSP00000359655.3

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000581

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000519

AC:

AN:

154094

AF XY:

0.0000735

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000657

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1394772

Hom.:

Cov.:

AF XY:

0.0000160

AC XY:

AN XY:

687910

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31310

American (AMR)

AF:

0.00

AC:

AN:

35320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25082

East Asian (EAS)

AF:

0.000451

AC:

AN:

35468

South Asian (SAS)

AF:

0.0000381

AC:

AN:

78652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

9.29e-7

AC:

AN:

1076204

Other (OTH)

AF:

0.0000173

AC:

AN:

57810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

151968

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41488

American (AMR)

AF:

0.00

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000583

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67956

Other (OTH)

AF:

0.00

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000388

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000814

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinal dystrophy

Pathogenic:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

not specified

Uncertain:1

Dec 15, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: EYS c.2892A>C (p.Glu964Asp) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. c.2892A>C has been reported in the literature as co-occurring with EYS c.2886C>G (p.Phe962Leu) in all instances ascertained among individuals affected with features of Leber congenital amaurosis (LCA) (example, Eisenberger_2013) or Retinitis Pigmentosa (example, Koyanagi_2019, Numa_2020, Gao_2022). In at-least two of these ascertainments, this variant combination also occurred along with a third EYS allele, again without phase specifications, among individuals affected with Retinitis Pigmentosa (n=2, c.8868delT (p.Ala2957fs), Koyanagi_2019 and n=1, c.2582G>A (p.Gly843Asp), Numa_2020). Furthermore, this variant combination also occurred without phase specifications, and therefore as a non-informative genotype alongside a majority concordant benign/likely benign EYS variant c.5510G>C (p.Trp1837Ser) in an individual with LCA (Eisenberger_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa or Leber congenital amaurosis. Both these variant alleles are found at a frequency of 5.2e-05 in 154094 and 153916 control chromosomes respectively in the gnomAD (v2) database, further supporting a co-occuring haplotype. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24265693, 34689181, 31213501, 33247286). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant in isolation was classified as uncertain significance.

not provided

Uncertain:1

Oct 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 964 of the EYS protein (p.Glu964Asp). This variant is present in population databases (rs762212630, gnomAD 0.06%). This missense change has been observed in individual(s) with EYS-related conditions (PMID: 24265693, 33247286). ClinVar contains an entry for this variant (Variation ID: 554346). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EYS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Retinitis pigmentosa 25

Uncertain:1

Oct 16, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.42

CADD

Benign

4.4

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.45

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.4

PhyloP100

0.31

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.8

REVEL

Benign

0.26

Sift

Benign

0.063

Sift4G

Uncertain

0.038

Polyphen

0.58

Vest4

0.23

MutPred

0.47

Loss of ubiquitination at K969 (P = 0.0768)

MVP

0.37

MPC

0.060

ClinPred

0.059

GERP RS

2.7

Varity_R

0.10

gMVP

0.74

Mutation Taster

=50/50

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over