rs9345601

chr6-65296077-G-Achr6-65296077-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001142800.2(EYS):c.1809C>T(p.Val603=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 1,548,970 control chromosomes in the GnomAD database, including 271,379 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V603V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.52 (22770 hom., cov: 33)
  • Exomes 𝑓: 0.59 (248609 hom.)
• Consequence: EYS NM_001142800.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.55

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-65296077-G-A is Benign according to our data. Variant chr6-65296077-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-65296077-G-A is described in Lovd as [Benign]. Variant chr6-65296077-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.1809C>T	p.Val603=	synonymous_variant	12/43	ENST00000503581.6
EYS	NM_001292009.2	c.1809C>T	p.Val603=	synonymous_variant	12/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.1809C>T	p.Val603=	synonymous_variant	12/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.1809C>T	p.Val603=	synonymous_variant	12/44	1		P2
EYS	ENST00000370615.3	n.247C>T		non_coding_transcript_exon_variant	2/2	3
EYS	ENST00000447127.1	n.265C>T		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.520 AC: 78928 AN: 151654 Hom.: 22755 Cov.: 33

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.667

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.906

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.581

GnomAD3 exomes AF: 0.625 AC: 97415 AN: 155874 Hom.: 31999 AF XY: 0.625 AC XY: 51566 AN XY: 82540

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.763

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.917

Gnomad SAS exome AF: 0.659

Gnomad FIN exome AF: 0.567

Gnomad NFE exome AF: 0.584

Gnomad OTH exome AF: 0.596

GnomAD4 exome AF: 0.591 AC: 825266 AN: 1397196 Hom.: 248609 Cov.: 41 AF XY: 0.593 AC XY: 408843 AN XY: 689088

Gnomad4 AFR exome AF: 0.265

Gnomad4 AMR exome AF: 0.745

Gnomad4 ASJ exome AF: 0.521

Gnomad4 EAS exome AF: 0.908

Gnomad4 SAS exome AF: 0.660

Gnomad4 FIN exome AF: 0.563

Gnomad4 NFE exome AF: 0.583

Gnomad4 OTH exome AF: 0.588

GnomAD4 genome AF: 0.520 AC: 78964 AN: 151774 Hom.: 22770 Cov.: 33 AF XY: 0.527 AC XY: 39100 AN XY: 74168

Gnomad4 AFR AF: 0.275

Gnomad4 AMR AF: 0.668

Gnomad4 ASJ AF: 0.524

Gnomad4 EAS AF: 0.906

Gnomad4 SAS AF: 0.681

Gnomad4 FIN AF: 0.570

Gnomad4 NFE AF: 0.583

Gnomad4 OTH AF: 0.586

Alfa AF: 0.561 Hom.: 9059

Bravo AF: 0.520

Asia WGS AF: 0.761 AC: 2640 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 17, 2014	- -
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:4

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Retinitis pigmentosa Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

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
BayesDel_noAF	Benign	-0.86
Cadd	Benign	3.0
Dann	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs9345601; hg19: chr6-66005970;