rs12193967

chr6-65495052-G-Achr6-65495052-G-Cchr6-65495052-G-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.359C>T(p.Thr120Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,613,900 control chromosomes in the GnomAD database, including 37,656 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. T120R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2880 hom., cov: 33)
  • Exomes 𝑓: 0.21 (34776 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0200

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=0.0052424073).
• BP6: Variant 6-65495052-G-A is Benign according to our data. Variant chr6-65495052-G-A is described in ClinVar as [Benign]. Clinvar id is 137261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-65495052-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.359C>T	p.Thr120Met	missense_variant	4/43	ENST00000503581.6
EYS	NM_001292009.2	c.359C>T	p.Thr120Met	missense_variant	4/44
EYS	NM_001142801.2	c.359C>T	p.Thr120Met	missense_variant	4/12
EYS	NM_198283.2	c.359C>T	p.Thr120Met	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.359C>T	p.Thr120Met	missense_variant	4/43	5	NM_001142800.2	A2

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26535 AN: 152026 Hom.: 2880 Cov.: 33

Gnomad AFR AF: 0.0401

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.223

GnomAD3 exomes AF: 0.209 AC: 52423 AN: 251270 Hom.: 5991 AF XY: 0.207 AC XY: 28151 AN XY: 135802

Gnomad AFR exome AF: 0.0370

Gnomad AMR exome AF: 0.264

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.247

Gnomad SAS exome AF: 0.160

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.214 AC: 312650 AN: 1461754 Hom.: 34776 Cov.: 34 AF XY: 0.212 AC XY: 154514 AN XY: 727198

Gnomad4 AFR exome AF: 0.0364

Gnomad4 AMR exome AF: 0.262

Gnomad4 ASJ exome AF: 0.246

Gnomad4 EAS exome AF: 0.254

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.220

Gnomad4 NFE exome AF: 0.219

Gnomad4 OTH exome AF: 0.213

GnomAD4 genome AF: 0.174 AC: 26538 AN: 152146 Hom.: 2880 Cov.: 33 AF XY: 0.177 AC XY: 13132 AN XY: 74372

Gnomad4 AFR AF: 0.0400

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.271

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.220

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.220

Alfa AF: 0.208 Hom.: 8561

Bravo AF: 0.173

TwinsUK AF: 0.219 AC: 811

ALSPAC AF: 0.221 AC: 852

ESP6500AA AF: 0.0449 AC: 198

ESP6500EA AF: 0.220 AC: 1891

ExAC AF: 0.203 AC: 24587

Asia WGS AF: 0.186 AC: 649 AN: 3478

EpiCase AF: 0.219

EpiControl AF: 0.218

ClinVar

Significance: Benign

Submissions summary: Benign:10

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)	Jun 12, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 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 25 Benign:2

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	Genome-Nilou Lab	Jul 01, 2021	- -

Retinitis pigmentosa Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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

- -

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	0.081
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	4.2
Dann	Uncertain	1.0
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.56	T;T;T;T
MetaRNN	Benign	0.0052	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.55	N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.92	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.19	T;T;T;T
Sift4G	Uncertain	0.039	D;D;T;T
Polyphen		0.063	B;.;.;B
Vest4		0.055
MPC		0.043
ClinPred		0.013	T
GERP RS		-1.7
Varity_R		0.015
gMVP		0.17

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: rs12193967; hg19: chr6-66204945; COSMIC: COSV60981231;