rs16895517

Variant names:

• chr6-64590250-G-C
• rs16895517
• NM_001142800.2:c.5617C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001142800.2(EYS):​c.5617C>G​(p.Leu1873Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,547,842 control chromosomes in the GnomAD database, including 13,774 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1873R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.098 (913 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12861 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.00600
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• EYS-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• retinitis pigmentosa 25

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017262399).
• BP6: Variant 6-64590250-G-C is Benign according to our data. Variant chr6-64590250-G-C is described in ClinVar as Benign. ClinVar VariationId is 93618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142800.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	NM_001142800.2	MANE Select	c.5617C>G	p.Leu1873Val	missense	Exon 26 of 43	NP_001136272.1
	EYS	NM_001292009.2		c.5617C>G	p.Leu1873Val	missense	Exon 26 of 44	NP_001278938.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	ENST00000503581.6	TSL:5 MANE Select	c.5617C>G	p.Leu1873Val	missense	Exon 26 of 43	ENSP00000424243.1
	EYS	ENST00000370621.7	TSL:1	c.5617C>G	p.Leu1873Val	missense	Exon 26 of 44	ENSP00000359655.3

Frequencies

GnomAD3 genomes AF: 0.0985 AC: 14972 AN: 152066 Hom.: 916 Cov.: 32

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0723

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0736

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.0967

GnomAD2 exomes AF: 0.118 AC: 17874 AN: 151430 AF XY: 0.119

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.0822

Gnomad EAS exome AF: 0.175

Gnomad FIN exome AF: 0.0820

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.132 AC: 184174 AN: 1395658 Hom.: 12861 Cov.: 33 AF XY: 0.132 AC XY: 90609 AN XY: 688162

African (AFR) AF: 0.0200 AC: 628 AN: 31420

American (AMR) AF: 0.135 AC: 4762 AN: 35354

Ashkenazi Jewish (ASJ) AF: 0.0797 AC: 1988 AN: 24942

East Asian (EAS) AF: 0.145 AC: 5163 AN: 35696

South Asian (SAS) AF: 0.104 AC: 8224 AN: 78852

European-Finnish (FIN) AF: 0.0808 AC: 3974 AN: 49188

Middle Eastern (MID) AF: 0.0573 AC: 325 AN: 5670

European-Non Finnish (NFE) AF: 0.141 AC: 151985 AN: 1076736

Other (OTH) AF: 0.123 AC: 7125 AN: 57800

GnomAD4 genome AF: 0.0983 AC: 14966 AN: 152184 Hom.: 913 Cov.: 32 AF XY: 0.0967 AC XY: 7190 AN XY: 74390

African (AFR) AF: 0.0279 AC: 1159 AN: 41552

American (AMR) AF: 0.123 AC: 1874 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 251 AN: 3470

East Asian (EAS) AF: 0.166 AC: 855 AN: 5160

South Asian (SAS) AF: 0.112 AC: 543 AN: 4828

European-Finnish (FIN) AF: 0.0736 AC: 781 AN: 10612

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9185 AN: 67998

Other (OTH) AF: 0.0957 AC: 202 AN: 2110

Alfa AF: 0.126 Hom.: 1015

Bravo AF: 0.102

TwinsUK AF: 0.135 AC: 499

ALSPAC AF: 0.128 AC: 494

ESP6500AA AF: 0.0282 AC: 39

ESP6500EA AF: 0.140 AC: 445

ExAC AF: 0.0948 AC: 2078

Asia WGS AF: 0.121 AC: 421 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Aug 11, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 25, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Retinitis pigmentosa Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.1
DANN	Benign	0.24
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.0060
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.088
Sift	Benign	0.61	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.021
MPC		0.0097
ClinPred		0.00026	T
GERP RS		2.0
Varity_R		0.040
gMVP		0.0094
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16895517; hg19: chr6-65300143; COSMIC: COSV107369956; COSMIC: COSV107369956;