rs974110

Variant names:

• chr6-65402516-A-G
• rs974110
• NM_001142800.2:c.1146T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001142800.2(EYS):​c.1146T>C​(p.Asn382Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 1,529,430 control chromosomes in the GnomAD database, including 201,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20917 hom., cov: 32)
  • Exomes 𝑓: 0.51 (180371 hom.)
• Consequence: EYS NM_001142800.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.00200

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-65402516-A-G is Benign according to our data. Variant chr6-65402516-A-G is described in ClinVar as [Benign]. Clinvar id is 137262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-65402516-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.002 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2	c.1146T>C	p.Asn382Asn	synonymous_variant	Exon 7 of 43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.1146T>C	p.Asn382Asn	synonymous_variant	Exon 7 of 44		NP_001278938.1
EYS	NM_001142801.2	c.1146T>C	p.Asn382Asn	synonymous_variant	Exon 7 of 12		NP_001136273.1
EYS	NM_198283.2	c.1146T>C	p.Asn382Asn	synonymous_variant	Exon 6 of 10		NP_938024.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.1146T>C	p.Asn382Asn	synonymous_variant	Exon 7 of 43	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.1146T>C	p.Asn382Asn	synonymous_variant	Exon 7 of 44	1		ENSP00000359655.3
EYS	ENST00000393380.6	c.1146T>C	p.Asn382Asn	synonymous_variant	Exon 7 of 12	1		ENSP00000377042.2
EYS	ENST00000342421.9	c.1146T>C	p.Asn382Asn	synonymous_variant	Exon 5 of 9	1		ENSP00000341818.5

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79538 AN: 151706 Hom.: 20891 Cov.: 32

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.538

Gnomad ASJ AF: 0.575

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.526

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.528

GnomAD3 exomes AF: 0.519 AC: 129770 AN: 249798 Hom.: 33944 AF XY: 0.519 AC XY: 70069 AN XY: 135058

Gnomad AFR exome AF: 0.528

Gnomad AMR exome AF: 0.558

Gnomad ASJ exome AF: 0.578

Gnomad EAS exome AF: 0.443

Gnomad SAS exome AF: 0.527

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.508

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.510 AC: 702437 AN: 1377606 Hom.: 180371 Cov.: 26 AF XY: 0.511 AC XY: 352198 AN XY: 689744

Gnomad4 AFR exome AF: 0.532

Gnomad4 AMR exome AF: 0.554

Gnomad4 ASJ exome AF: 0.570

Gnomad4 EAS exome AF: 0.444

Gnomad4 SAS exome AF: 0.526

Gnomad4 FIN exome AF: 0.536

Gnomad4 NFE exome AF: 0.506

Gnomad4 OTH exome AF: 0.511

GnomAD4 genome AF: 0.524 AC: 79619 AN: 151824 Hom.: 20917 Cov.: 32 AF XY: 0.529 AC XY: 39214 AN XY: 74188

Gnomad4 AFR AF: 0.536

Gnomad4 AMR AF: 0.538

Gnomad4 ASJ AF: 0.575

Gnomad4 EAS AF: 0.468

Gnomad4 SAS AF: 0.537

Gnomad4 FIN AF: 0.539

Gnomad4 NFE AF: 0.511

Gnomad4 OTH AF: 0.526

Alfa AF: 0.516 Hom.: 29739

Bravo AF: 0.524

Asia WGS AF: 0.475 AC: 1648 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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

Significance: Benign

Review Status: no assertion criteria provided

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

- -

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. -

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

- -

Retinitis pigmentosa 25 Benign:2

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

- -

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
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.27

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: rs974110; hg19: chr6-66112409; COSMIC: COSV60985754;