rs201652272

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001142800.2(EYS):​c.2234A>G​(p.Asn745Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,551,278 control chromosomes in the GnomAD database, including 6 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 6 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:10B:1

Conservation

PhyloP100: 2.94
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.027632952).
BS2
High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EYSNM_001142800.2 linkuse as main transcriptc.2234A>G p.Asn745Ser missense_variant 14/43 ENST00000503581.6 NP_001136272.1 Q5T1H1-1
EYSNM_001292009.2 linkuse as main transcriptc.2234A>G p.Asn745Ser missense_variant 14/44 NP_001278938.1 Q5T1H1-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EYSENST00000503581.6 linkuse as main transcriptc.2234A>G p.Asn745Ser missense_variant 14/435 NM_001142800.2 ENSP00000424243.1 Q5T1H1-1
EYSENST00000370621.7 linkuse as main transcriptc.2234A>G p.Asn745Ser missense_variant 14/441 ENSP00000359655.3 Q5T1H1-3

Frequencies

GnomAD3 genomes
AF:
0.000670
AC:
102
AN:
152172
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000410
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00104
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000831
AC:
131
AN:
157658
Hom.:
0
AF XY:
0.000721
AC XY:
60
AN XY:
83274
show subpopulations
Gnomad AFR exome
AF:
0.000491
Gnomad AMR exome
AF:
0.000283
Gnomad ASJ exome
AF:
0.00141
Gnomad EAS exome
AF:
0.0000917
Gnomad SAS exome
AF:
0.0000439
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00166
Gnomad OTH exome
AF:
0.000898
GnomAD4 exome
AF:
0.00126
AC:
1767
AN:
1398988
Hom.:
6
Cov.:
30
AF XY:
0.00119
AC XY:
820
AN XY:
690008
show subpopulations
Gnomad4 AFR exome
AF:
0.000190
Gnomad4 AMR exome
AF:
0.000420
Gnomad4 ASJ exome
AF:
0.00119
Gnomad4 EAS exome
AF:
0.0000561
Gnomad4 SAS exome
AF:
0.0000126
Gnomad4 FIN exome
AF:
0.0000203
Gnomad4 NFE exome
AF:
0.00153
Gnomad4 OTH exome
AF:
0.00102
GnomAD4 genome
AF:
0.000670
AC:
102
AN:
152290
Hom.:
0
Cov.:
32
AF XY:
0.000671
AC XY:
50
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.000409
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00104
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00134
Hom.:
1
Bravo
AF:
0.000801
TwinsUK
AF:
0.00216
AC:
8
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00145
AC:
2
ESP6500EA
AF:
0.000629
AC:
2
ExAC
AF:
0.000476
AC:
12

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:10Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Retinitis pigmentosa 25 Pathogenic:1Uncertain:4
Likely pathogenic, criteria provided, single submitterresearchOcular Genomics Institute, Massachusetts Eye and EarApr 08, 2021The EYS c.2234A>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PM3. Based on this evidence we have classified this variant as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJun 06, 2024- -
Uncertain significance, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+Sep 01, 2016- -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jul 20, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterAug 22, 2022- -
not provided Pathogenic:1Uncertain:3Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2022EYS: BP4 -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 13, 2014- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 25, 2022This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 745 of the EYS protein (p.Asn745Ser). This variant is present in population databases (rs201652272, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive retinitis pigmentosa, and autosomal recessive cone-rod dystrophy (PMID: 21069908, 26103963). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 194357). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C45". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 21, 2023In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one homozygous clinically unaffected adult relative of an individual referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 34426522, 20333770, 30755224, 30487145, 21069908, 32037395, 33833316, 31574917, 26659599, 26103963, 28224992, 30937429, 21519034, 32483926) -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 22, 2022Variant summary: EYS c.2234A>G (p.Asn745Ser) results in a conservative amino acid change located in the EGF-like calcium-binding domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 157658 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.00083 vs 0.0034), allowing no conclusion about variant significance. c.2234A>G has been reported in the literature in individuals affected with Retinitis Pigmentosa. These reports do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic n=2, VUS n=4). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBlueprint GeneticsJan 31, 2019- -
Retinitis pigmentosa Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaAug 27, 2016The EYS c.2234A>G (p.Asn745Ser) variant is a missense variant that has been reported in four studies and identified in a compound heterozygous state with a stop-gained variant in two siblings with autosomal recessive retinitis pigmentosa and in one individual with cone and cone-rod dystrophy as well as in a heterozygous state in two individuals with retinitis pigmentosa in whom a second variant could not be found (Audo et al. 2010; Barragan et al. 2010; Pieras et al. 2011; Boulanger-Scemama et al. 2015). The p.Asn745Ser variant was absent from 728 controls and is reported at a frequency of 0.00134 in the African population of the Exome Aggregation Consortium. Based on the evidence, the p.Asn745Ser variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Benign
0.038
.;T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.32
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.66
T;T
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.028
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.5
L;L
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-1.5
N;N
REVEL
Benign
0.14
Sift
Benign
0.15
T;T
Sift4G
Uncertain
0.018
D;D
Polyphen
0.18
B;.
Vest4
0.30
MVP
0.27
MPC
0.050
ClinPred
0.028
T
GERP RS
0.17
Varity_R
0.057
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs201652272; hg19: chr6-65707500; API