chr6-65494921-G-A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001142800.2(EYS):​c.490C>T​(p.Arg164*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,940 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R164R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

EYS
NM_001142800.2 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 0.716

Publications

9 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 6-65494921-G-A is Pathogenic according to our data. Variant chr6-65494921-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 197186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EYSNM_001142800.2 linkc.490C>T p.Arg164* stop_gained Exon 4 of 43 ENST00000503581.6 NP_001136272.1 Q5T1H1-1
EYSNM_001292009.2 linkc.490C>T p.Arg164* stop_gained Exon 4 of 44 NP_001278938.1 Q5T1H1-3
EYSNM_001142801.2 linkc.490C>T p.Arg164* stop_gained Exon 4 of 12 NP_001136273.1 Q5T1H1-4
EYSNM_198283.2 linkc.490C>T p.Arg164* stop_gained Exon 3 of 10 NP_938024.1 Q5T1H1-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EYSENST00000503581.6 linkc.490C>T p.Arg164* stop_gained Exon 4 of 43 5 NM_001142800.2 ENSP00000424243.1 Q5T1H1-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152082
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000796
AC:
2
AN:
251220
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1461858
Hom.:
0
Cov.:
31
AF XY:
0.0000179
AC XY:
13
AN XY:
727224
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.000104
AC:
9
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000540
AC:
6
AN:
1111990
Other (OTH)
AF:
0.0000828
AC:
5
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.454
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152082
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74302
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41418
American (AMR)
AF:
0.00
AC:
0
AN:
15260
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10598
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68014
Other (OTH)
AF:
0.00
AC:
0
AN:
2086
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.350
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000149
Hom.:
0
Bravo
AF:
0.0000189

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinitis pigmentosa 25 Pathogenic:6
Sep 22, 2021
Illumina Laboratory Services, Illumina
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The EYS c.490C>T (p.Arg164Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The variant has been reported in a compound heterozygous state in at least five individuals, including two siblings, affected with retinitis pigmentosa (O'Sullivan et al. 2012; Chen et al. 2015; McGuigan et al. 2017). The variant is reported at a frequency of 0.000008 in the Total population of the Genome Aggregation database (version 2.1.1), though this is based on only two occurrences in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence, the p.Arg164Ter variant is classified as pathogenic for autosomal recessive retinitis pigmentosa. -

Jan 03, 2022
3billion
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000197186, PMID:22581970). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 28, 2021
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 08, 2020
Natera, Inc.
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Feb 28, 2024
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Pathogenic:3
Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 12, 2017
Eurofins Ntd Llc (ga)
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg164*) 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 (rs794727631, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with retinitis pigmentosa (PMID: 22581970, 25753737). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197186). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa Pathogenic:2
Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

Oct 01, 2024
Lab De Baere, Eye and Developmental Genetics Lab, Ghent University
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

ACMG/AMP guidelines: PM2, PVS1, PP1, PM3_1 -

Retinal dystrophy Pathogenic:1
Jan 01, 2021
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
34
DANN
Uncertain
1.0
Eigen
Uncertain
0.38
Eigen_PC
Benign
0.13
FATHMM_MKL
Benign
0.45
N
PhyloP100
0.72
Vest4
0.73
GERP RS
2.6
Mutation Taster
=0/200
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794727631; hg19: chr6-66204814; COSMIC: COSV60981344; API