rs61753610

chr6-65335034-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001142800.2(EYS):c.1712A>G(p.Gln571Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,611,088 control chromosomes in the GnomAD database, including 22,985 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1533 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21452 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.65

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.687973E-4).
• BP6: Variant 6-65335034-T-C is Benign according to our data. Variant chr6-65335034-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 137265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-65335034-T-C is described in Lovd as [Benign]. Variant chr6-65335034-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.1712A>G	p.Gln571Arg	missense_variant	11/43	ENST00000503581.6
EYS	NM_001292009.2	c.1712A>G	p.Gln571Arg	missense_variant	11/44
EYS	NM_001142801.2	c.1712A>G	p.Gln571Arg	missense_variant	11/12
EYS	NM_198283.2	c.1712A>G	p.Gln571Arg	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.1712A>G	p.Gln571Arg	missense_variant	11/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.1712A>G	p.Gln571Arg	missense_variant	11/44	1		P2
EYS	ENST00000393380.6	c.1712A>G	p.Gln571Arg	missense_variant	11/12	1
EYS	ENST00000342421.9	c.1712A>G	p.Gln571Arg	missense_variant	9/9	1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20050 AN: 151684 Hom.: 1530 Cov.: 32

Gnomad AFR AF: 0.0337

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.159 AC: 39776 AN: 250118 Hom.: 3529 AF XY: 0.162 AC XY: 21890 AN XY: 135200

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.113

Gnomad SAS exome AF: 0.177

Gnomad FIN exome AF: 0.180

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.168 AC: 244783 AN: 1459286 Hom.: 21452 Cov.: 31 AF XY: 0.168 AC XY: 122279 AN XY: 726080

Gnomad4 AFR exome AF: 0.0267

Gnomad4 AMR exome AF: 0.168

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.174

Gnomad4 OTH exome AF: 0.157

GnomAD4 genome AF: 0.132 AC: 20055 AN: 151802 Hom.: 1533 Cov.: 32 AF XY: 0.133 AC XY: 9831 AN XY: 74166

Gnomad4 AFR AF: 0.0336

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.182

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.134

Alfa AF: 0.164 Hom.: 3431

Bravo AF: 0.125

TwinsUK AF: 0.168 AC: 624

ALSPAC AF: 0.173 AC: 667

ESP6500AA AF: 0.0336 AC: 148

ESP6500EA AF: 0.173 AC: 1485

ExAC AF: 0.156 AC: 18983

Asia WGS AF: 0.148 AC: 514 AN: 3478

EpiCase AF: 0.176

EpiControl AF: 0.180

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Retinitis pigmentosa 25 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Mar 04, 2015	- -

Retinitis pigmentosa Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	6.5
Dann	Benign	0.94
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.43	T;T;T;T
MetaRNN	Benign	0.00087	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.63	N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.033
Sift	Benign	0.40	T;T;T;T
Sift4G	Uncertain	0.0030	D;D;T;T
Polyphen		0.22	B;.;.;B
Vest4		0.19
MPC		0.0099
ClinPred		0.0048	T
GERP RS		2.2
Varity_R		0.061
gMVP		0.62

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

Other links and lift over

dbSNP: rs61753610; hg19: chr6-66044927; COSMIC: COSV60985736;