rs762212630

Variant names:

• chr6-64886797-T-A
• NM_001142800.2:c.2892A>T

Your query was ambiguous. Multiple possible variants found:

• chr6-64886797-T-A
• chr6-64886797-T-C
• chr6-64886797-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PS1 PM1 PM2 BP4_Moderate

The NM_001142800.2(EYS):​c.2892A>T​(p.Glu964Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.314

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 Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript NM_001142800.2 (EYS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a domain EGF-like 14; calcium-binding (size 36) in uniprot entity EYS_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001142800.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21356231).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2	c.2892A>T	p.Glu964Asp	missense_variant	Exon 19 of 43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.2892A>T	p.Glu964Asp	missense_variant	Exon 19 of 44		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.2892A>T	p.Glu964Asp	missense_variant	Exon 19 of 43	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.2892A>T	p.Glu964Asp	missense_variant	Exon 19 of 44	1		ENSP00000359655.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EYS protein function. This variant has not been reported in the literature in individuals affected with EYS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 964 of the EYS protein (p.Glu964Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	.;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.45	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.27
Sift	Benign	0.063	T;T
Sift4G	Uncertain	0.038	D;D
Polyphen		0.58	P;.
Vest4		0.23
MutPred		0.47		Loss of ubiquitination at K969 (P = 0.0768);Loss of ubiquitination at K969 (P = 0.0768);
MVP		0.37
MPC		0.060
ClinPred		0.48	T
GERP RS		2.7
Varity_R		0.10
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr6-65596690;