rs624851

Variant names:

• chr6-64591611-A-G
• rs624851
• NM_001142800.2:c.4256T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-64591611-A-G
• chr6-64591611-A-T

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.4256T>C​(p.Leu1419Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 1,550,802 control chromosomes in the GnomAD database, including 402,452 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.77 (45597 hom., cov: 30)
  • Exomes 𝑓: 0.71 (356855 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.05
• Publications: 30 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=8.1337487E-7).
• BP6: Variant 6-64591611-A-G is Benign according to our data. Variant chr6-64591611-A-G is described in ClinVar as Benign. ClinVar VariationId is 93611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.934 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2	c.4256T>C	p.Leu1419Ser	missense_variant	Exon 26 of 43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.4256T>C	p.Leu1419Ser	missense_variant	Exon 26 of 44		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.4256T>C	p.Leu1419Ser	missense_variant	Exon 26 of 43	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.4256T>C	p.Leu1419Ser	missense_variant	Exon 26 of 44	1		ENSP00000359655.3

Frequencies

GnomAD3 genomes AF: 0.767 AC: 116364 AN: 151782 Hom.: 45533 Cov.: 30

Gnomad AFR AF: 0.942

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.745

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.772

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.692

Gnomad OTH AF: 0.711

GnomAD2 exomes AF: 0.729 AC: 111796 AN: 153440 AF XY: 0.728

Gnomad AFR exome AF: 0.950

Gnomad AMR exome AF: 0.777

Gnomad ASJ exome AF: 0.642

Gnomad EAS exome AF: 0.659

Gnomad FIN exome AF: 0.704

Gnomad NFE exome AF: 0.692

Gnomad OTH exome AF: 0.712

GnomAD4 exome AF: 0.713 AC: 996812 AN: 1398902 Hom.: 356855 Cov.: 56 AF XY: 0.713 AC XY: 492035 AN XY: 689970

African (AFR) AF: 0.948 AC: 29938 AN: 31582

American (AMR) AF: 0.775 AC: 27681 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 16300 AN: 25158

East Asian (EAS) AF: 0.699 AC: 24990 AN: 35734

South Asian (SAS) AF: 0.778 AC: 61620 AN: 79224

European-Finnish (FIN) AF: 0.709 AC: 34945 AN: 49266

Middle Eastern (MID) AF: 0.635 AC: 3616 AN: 5698

European-Non Finnish (NFE) AF: 0.701 AC: 756282 AN: 1078554

Other (OTH) AF: 0.715 AC: 41440 AN: 57984

GnomAD4 genome AF: 0.767 AC: 116486 AN: 151900 Hom.: 45597 Cov.: 30 AF XY: 0.766 AC XY: 56826 AN XY: 74212

African (AFR) AF: 0.942 AC: 39070 AN: 41480

American (AMR) AF: 0.745 AC: 11339 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 2255 AN: 3468

East Asian (EAS) AF: 0.666 AC: 3417 AN: 5134

South Asian (SAS) AF: 0.772 AC: 3718 AN: 4816

European-Finnish (FIN) AF: 0.702 AC: 7407 AN: 10552

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.692 AC: 47001 AN: 67930

Other (OTH) AF: 0.714 AC: 1503 AN: 2106

Alfa AF: 0.712 Hom.: 124682

Bravo AF: 0.777

TwinsUK AF: 0.697 AC: 2586

ALSPAC AF: 0.708 AC: 2728

ESP6500AA AF: 0.942 AC: 1304

ESP6500EA AF: 0.701 AC: 2232

ExAC AF: 0.737 AC: 15406

Asia WGS AF: 0.745 AC: 2590 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Aug 09, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 05, 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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinitis pigmentosa 25 Benign:4

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2015

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.1
DANN	Benign	0.19
DEOGEN2	Benign	0.040	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.19	T;T
MetaRNN	Benign	8.1e-7	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		1.0
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.12	N;N
REVEL	Benign	0.25
Sift	Benign	0.034	D;T
Sift4G	Benign	0.32	T;T
Polyphen		0.010	B;B
Vest4		0.029
MPC		0.0094
ClinPred		0.0043	T
GERP RS		0.38
Varity_R		0.037
gMVP		0.045
Mutation Taster		=99/1	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: rs624851; hg19: chr6-65301504; COSMIC: COSV58195780; COSMIC: COSV58195780;