rs762212630

Positions:

chr6-64886797-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

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. 14/21 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 same amino acid change has been previously reported as Uncertain significancein 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

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 Uncertain_significance. Variant got 0 ACMG points.

PM1

In a domain EGF-like 14; calcium-binding (size 36) in uniprot entity EYS_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_001142800.2

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057252854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2 linkuse as main transcript	c.2892A>C	p.Glu964Asp	missense_variant	19/43	ENST00000503581.6
EYS	NM_001292009.2 linkuse as main transcript	c.2892A>C	p.Glu964Asp	missense_variant	19/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6 linkuse as main transcript	c.2892A>C	p.Glu964Asp	missense_variant	19/43	5	NM_001142800.2	A2	Q5T1H1-1
EYS	ENST00000370621.7 linkuse as main transcript	c.2892A>C	p.Glu964Asp	missense_variant	19/44	1		P2	Q5T1H1-3

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

GnomAD3 exomes

AF:

0.0000519

AC:

AN:

154094

Hom.:

AF XY:

0.0000735

AC XY:

AN XY:

81642

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 SAS exome

AF:

0.0000444

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000451

Gnomad4 SAS exome

AF:

0.0000381

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.29e-7

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151968

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000583

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Pathogenic, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 15, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 16, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.42

CADD

Benign

4.4

DANN

Uncertain

0.99

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.45

T;T

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.057

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.26

Sift

Benign

0.063

T;T

Sift4G

Uncertain

0.038

D;D

Polyphen

0.58

P;.

Vest4

0.23

MutPred

0.47

Loss of ubiquitination at K969 (P = 0.0768);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

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