chr6-63864209-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001142800.2(EYS):c.7205G>A(p.Arg2402Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000881 in 1,543,496 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000093 ( 2 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.09

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04785523).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.7205G>A	p.Arg2402Lys	missense_variant	Exon 36 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 link	c.7205G>A	p.Arg2402Lys	missense_variant	Exon 36 of 44		NP_001278938.1	Q5T1H1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EYS	ENST00000503581.6 link	c.7205G>A	p.Arg2402Lys	missense_variant	Exon 36 of 43	5	NM_001142800.2	ENSP00000424243.1	Q5T1H1-1
EYS	ENST00000370621.7 link	c.7205G>A	p.Arg2402Lys	missense_variant	Exon 36 of 44	1		ENSP00000359655.3	Q5T1H1-3
EYS	ENST00000398580.3 link	c.518G>A	p.Arg173Lys	missense_variant	Exon 4 of 10	5		ENSP00000381585.3	H0Y3Q4

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152194

Hom.:

Cov.:

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:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000191

AC:

AN:

151860

Hom.:

AF XY:

0.000274

AC XY:

AN XY:

80312

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 SAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000934

AC:

130

AN:

1391184

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

105

AN XY:

685014

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.31e-7

Gnomad4 OTH exome

AF:

0.0000347

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.000440

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with lysine at codon 2402 of the EYS protein (p.Arg2402Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs766515998, ExAC 0.2%). This missense change has been observed in individual(s) with retinal dystrophy (PMID: 20237254). ClinVar contains an entry for this variant (Variation ID: 549918). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Retinitis pigmentosa 25

Uncertain:1

Mar 30, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.024

.;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.048

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.99

L;L

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.74

N;N

REVEL

Benign

0.26

Sift

Benign

0.33

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.86

P;P

Vest4

0.50

MutPred

0.66

Gain of ubiquitination at R2402 (P = 0.0198);Gain of ubiquitination at R2402 (P = 0.0198);

MVP

0.17

MPC

0.019

ClinPred

0.075

GERP RS

1.6

Varity_R

0.11

gMVP

0.76

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

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