NM_001142800.2:c.1891G>A

Variant names:

• chr6-65295995-C-T
• rs9342464
• NM_001142800.2:c.1891G>A

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.1891G>A​(p.Gly631Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 1,550,630 control chromosomes in the GnomAD database, including 271,627 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G631G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.52 (22765 hom., cov: 32)
  • Exomes 𝑓: 0.59 (248862 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.90
• 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=1.4348618E-6).
• BP6: Variant 6-65295995-C-T is Benign according to our data. Variant chr6-65295995-C-T is described in ClinVar as [Benign]. Clinvar id is 137267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2	c.1891G>A	p.Gly631Ser	missense_variant	Exon 12 of 43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.1891G>A	p.Gly631Ser	missense_variant	Exon 12 of 44		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.1891G>A	p.Gly631Ser	missense_variant	Exon 12 of 43	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.1891G>A	p.Gly631Ser	missense_variant	Exon 12 of 44	1		ENSP00000359655.3
EYS	ENST00000370615.3	n.329G>A		non_coding_transcript_exon_variant	Exon 2 of 2	3
EYS	ENST00000447127.1	n.347G>A		non_coding_transcript_exon_variant	Exon 3 of 3	4

Frequencies

GnomAD3 genomes AF: 0.520 AC: 78876 AN: 151592 Hom.: 22751 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.906

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.580

GnomAD2 exomes AF: 0.625 AC: 98325 AN: 157416 AF XY: 0.625

Gnomad AFR exome AF: 0.263

Gnomad AMR exome AF: 0.763

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.917

Gnomad FIN exome AF: 0.566

Gnomad NFE exome AF: 0.584

Gnomad OTH exome AF: 0.595

GnomAD4 exome AF: 0.591 AC: 826335 AN: 1398920 Hom.: 248862 Cov.: 56 AF XY: 0.593 AC XY: 409393 AN XY: 689948

African (AFR) AF: 0.266 AC: 8392 AN: 31578

American (AMR) AF: 0.745 AC: 26598 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13102 AN: 25152

East Asian (EAS) AF: 0.908 AC: 32450 AN: 35730

South Asian (SAS) AF: 0.660 AC: 52287 AN: 79190

European-Finnish (FIN) AF: 0.563 AC: 27778 AN: 49378

Middle Eastern (MID) AF: 0.542 AC: 3088 AN: 5698

European-Non Finnish (NFE) AF: 0.583 AC: 628516 AN: 1078456

Other (OTH) AF: 0.588 AC: 34124 AN: 58040

GnomAD4 genome AF: 0.520 AC: 78910 AN: 151710 Hom.: 22765 Cov.: 32 AF XY: 0.527 AC XY: 39084 AN XY: 74156

African (AFR) AF: 0.274 AC: 11345 AN: 41396

American (AMR) AF: 0.668 AC: 10159 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1817 AN: 3466

East Asian (EAS) AF: 0.906 AC: 4655 AN: 5140

South Asian (SAS) AF: 0.681 AC: 3285 AN: 4824

European-Finnish (FIN) AF: 0.571 AC: 6017 AN: 10540

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39568 AN: 67818

Other (OTH) AF: 0.586 AC: 1236 AN: 2110

Alfa AF: 0.574 Hom.: 82765

Bravo AF: 0.520

TwinsUK AF: 0.578 AC: 2142

ALSPAC AF: 0.581 AC: 2239

ESP6500AA AF: 0.301 AC: 416

ESP6500EA AF: 0.583 AC: 1856

ExAC AF: 0.561 AC: 13919

Asia WGS AF: 0.761 AC: 2641 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

- -

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

- -

Mar 17, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 25 Benign:4

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

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

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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 13, 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	0.067
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.1
DANN	Benign	0.60
DEOGEN2	Benign	0.024	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.35	T;T
MetaRNN	Benign	0.0000014	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		1.9
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.21
Sift	Benign	0.11	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.0	B;.
Vest4		0.13
MPC		0.0097
ClinPred		0.0050	T
GERP RS		1.7
Varity_R		0.025
gMVP		0.72
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: rs9342464; hg19: chr6-66005888; COSMIC: COSV107470333;