GeneBe

rs74419361

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_001142800.2(EYS):ā€‹c.2528G>Cā€‹(p.Gly843Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G843E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 7.1e-7 ( 0 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

8
7
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.15
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a domain EGF-like 11 (size 38) in uniprot entity EYS_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_001142800.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-64912597-C-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EYSNM_001142800.2 linkc.2528G>C p.Gly843Ala missense_variant Exon 16 of 43 ENST00000503581.6 NP_001136272.1 Q5T1H1-1
EYSNM_001292009.2 linkc.2528G>C p.Gly843Ala missense_variant Exon 16 of 44 NP_001278938.1 Q5T1H1-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EYSENST00000503581.6 linkc.2528G>C p.Gly843Ala missense_variant Exon 16 of 43 5 NM_001142800.2 ENSP00000424243.1 Q5T1H1-1
EYSENST00000370621.7 linkc.2528G>C p.Gly843Ala missense_variant Exon 16 of 44 1 ENSP00000359655.3 Q5T1H1-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.15e-7
AC:
1
AN:
1399086
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
690040
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.27e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.63
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.23
.;T
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.64
T;T
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
H;H
PrimateAI
Benign
0.43
T
PROVEAN
Pathogenic
-5.9
D;D
REVEL
Pathogenic
0.69
Sift
Uncertain
0.019
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;.
Vest4
0.46
MutPred
0.98
Loss of catalytic residue at P839 (P = 0.1103);Loss of catalytic residue at P839 (P = 0.1103);
MVP
0.56
MPC
0.062
ClinPred
0.97
D
GERP RS
5.0
Varity_R
0.39
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-65622490; API