rs752683070

Positions:

chr6-65405349-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001142800.2(EYS):c.881C>G(p.Ser294Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,608,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

EYS
NM_001142800.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.307

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-65405349-G-C is Pathogenic according to our data. Variant chr6-65405349-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EYS	NM_001142800.2 linkuse as main transcript	c.881C>G	p.Ser294Ter	stop_gained	6/43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2 linkuse as main transcript	c.881C>G	p.Ser294Ter	stop_gained	6/44		NP_001278938.1
EYS	NM_001142801.2 linkuse as main transcript	c.881C>G	p.Ser294Ter	stop_gained	6/12		NP_001136273.1
EYS	NM_198283.2 linkuse as main transcript	c.881C>G	p.Ser294Ter	stop_gained	5/10		NP_938024.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6 linkuse as main transcript	c.881C>G	p.Ser294Ter	stop_gained	6/43	5	NM_001142800.2	ENSP00000424243	A2	Q5T1H1-1
EYS	ENST00000370621.7 linkuse as main transcript	c.881C>G	p.Ser294Ter	stop_gained	6/44	1		ENSP00000359655	P2	Q5T1H1-3
EYS	ENST00000393380.6 linkuse as main transcript	c.881C>G	p.Ser294Ter	stop_gained	6/12	1		ENSP00000377042		Q5T1H1-4
EYS	ENST00000342421.9 linkuse as main transcript	c.881C>G	p.Ser294Ter	stop_gained	4/9	1		ENSP00000341818		Q5T1H1-2

Frequencies

GnomAD3 genomes

AF:

0.0000538

AC:

AN:

148792

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000173

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000681

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250524

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135452

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1459848

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726280

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000538

AC:

AN:

148792

Hom.:

Cov.:

AF XY:

0.0000554

AC XY:

AN XY:

72216

show subpopulations

Gnomad4 AFR

AF:

0.000173

Gnomad4 AMR

AF:

0.0000681

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 15, 2014	The p.Ser294X variant in EYS has not been previously reported in individuals with retinitis pigmentosa but has been identified in 0.038% (4/10520) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 294, which is predicted to lead to a truncated or absent protein. Complete loss of EYS function is an established disease mechanism in individuals with autosomal recessive retinitis pigmentosa. In summary, this variant meets our criteria to be classified as pathogenic for retinitis pigmentosa in an autosomal recessive manner. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2024

This sequence change creates a premature translational stop signal (p.Ser294*) in the EYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (rs752683070, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with EYS-related conditions. ClinVar contains an entry for this variant (Variation ID: 208579). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 24, 2019

- -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 04, 2023

Variant summary: EYS c.881C>G (p.Ser294X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 250524 control chromosomes (gnomAD). To our knowledge, no occurrence of c.881C>G in individuals affected with Retinitis Pigmentosa and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic (n=1) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Benign

0.13

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.15

MutationTaster

Benign

1.0

A;A;A;A;A;A

Vest4

0.90

GERP RS

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over