chr6-65295995-C-T

Position:

• chr6-65295995-C-T

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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 -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. Variant chr6-65295995-C-T is described in Lovd as [Benign].
• 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	Protein	UniProt
EYS	NM_001142800.2	c.1891G>A	p.Gly631Ser	missense_variant	12/43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.1891G>A	p.Gly631Ser	missense_variant	12/44		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.1891G>A	p.Gly631Ser	missense_variant	12/43	5	NM_001142800.2	ENSP00000424243	A2
EYS	ENST00000370621.7	c.1891G>A	p.Gly631Ser	missense_variant	12/44	1		ENSP00000359655	P2
EYS	ENST00000370615.3	n.329G>A		non_coding_transcript_exon_variant	2/2	3
EYS	ENST00000447127.1	n.347G>A		non_coding_transcript_exon_variant	3/3	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

GnomAD3 exomes AF: 0.625 AC: 98325 AN: 157416 Hom.: 32264 AF XY: 0.625 AC XY: 51904 AN XY: 83060

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 SAS exome AF: 0.660

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

Gnomad4 AFR exome AF: 0.266

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

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.668

Gnomad4 ASJ AF: 0.524

Gnomad4 EAS AF: 0.906

Gnomad4 SAS AF: 0.681

Gnomad4 FIN AF: 0.571

Gnomad4 NFE AF: 0.583

Gnomad4 OTH AF: 0.586

Alfa AF: 0.585 Hom.: 40544

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

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, 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	Eurofins Ntd Llc (ga)	Mar 17, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Retinitis pigmentosa 25 Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Mar 04, 2015	- -
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	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

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
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
MutationTaster	Benign	1.0	P;P;P
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

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: rs9342464; hg19: chr6-66005888;