rs62415825

chr6-64591274-C-T

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.4593G>A(p.Glu1531=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,551,080 control chromosomes in the GnomAD database, including 13,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (928 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12911 hom.)
• Consequence: EYS NM_001142800.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.395

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=-0.77).
• BP6: Variant 6-64591274-C-T is Benign according to our data. Variant chr6-64591274-C-T is described in ClinVar as [Benign]. Clinvar id is 93615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-64591274-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.395 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.4593G>A	p.Glu1531=	synonymous_variant	26/43	ENST00000503581.6
EYS	NM_001292009.2	c.4593G>A	p.Glu1531=	synonymous_variant	26/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.4593G>A	p.Glu1531=	synonymous_variant	26/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.4593G>A	p.Glu1531=	synonymous_variant	26/44	1		P2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15354 AN: 151988 Hom.: 931 Cov.: 32

Gnomad AFR AF: 0.0366

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.0723

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0742

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.0992

GnomAD3 exomes AF: 0.119 AC: 18242 AN: 153700 Hom.: 1238 AF XY: 0.119 AC XY: 9731 AN XY: 81556

Gnomad AFR exome AF: 0.0306

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.0820

Gnomad EAS exome AF: 0.175

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.0820

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.132 AC: 185120 AN: 1398974 Hom.: 12911 Cov.: 35 AF XY: 0.132 AC XY: 91042 AN XY: 689994

Gnomad4 AFR exome AF: 0.0303

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.0797

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.0808

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.124

GnomAD4 genome AF: 0.101 AC: 15349 AN: 152106 Hom.: 928 Cov.: 32 AF XY: 0.0993 AC XY: 7381 AN XY: 74356

Gnomad4 AFR AF: 0.0365

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.0723

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.0742

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.0982

Alfa AF: 0.128 Hom.: 1964

Bravo AF: 0.105

Asia WGS AF: 0.122 AC: 422 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 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. -

Retinitis pigmentosa Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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

- -

Retinitis pigmentosa 25 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

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	-0.77
Cadd	Benign	2.9
Dann	Benign	0.34

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: rs62415825; hg19: chr6-65301167; COSMIC: COSV58197760; COSMIC: COSV58197760;