6-64591894-G-T

Position:

• chr6-64591894-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001142800.2(EYS):​c.3973C>A​(p.Gln1325Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1325E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.11

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054107577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYS	NM_001142800.2	c.3973C>A	p.Gln1325Lys	missense_variant	26/43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.3973C>A	p.Gln1325Lys	missense_variant	26/44		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.3973C>A	p.Gln1325Lys	missense_variant	26/43	5	NM_001142800.2	ENSP00000424243	A2
EYS	ENST00000370621.7	c.3973C>A	p.Gln1325Lys	missense_variant	26/44	1		ENSP00000359655	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398208 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 689590

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: 9.28e-7

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 1325 of the EYS protein (p.Gln1325Lys). This variant is not present in population databases (gnomAD no frequency). 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: 1026174). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.0020
DANN	Benign	0.36
DEOGEN2	Benign	0.043	.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.21	T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.23
Sift	Benign	0.31	T;T
Sift4G	Benign	0.86	T;T
Polyphen		0.0	B;B
Vest4		0.087
MutPred		0.54		Gain of ubiquitination at Q1325 (P = 0.0211);Gain of ubiquitination at Q1325 (P = 0.0211);
MVP		0.099
MPC		0.0095
ClinPred		0.14	T
GERP RS		-2.6
Varity_R		0.050
gMVP		0.097

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

Other links and lift over

dbSNP: rs12663622; hg19: chr6-65301787;