6-65405253-C-T

Position:

• chr6-65405253-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001142800.2(EYS):​c.977G>A​(p.Ser326Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,613,202 control chromosomes in the GnomAD database, including 9 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (7 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:7
• Conservation: PhyloP100: 0.120

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006911695).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYS	NM_001142800.2	c.977G>A	p.Ser326Asn	missense_variant	6/43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.977G>A	p.Ser326Asn	missense_variant	6/44		NP_001278938.1
EYS	NM_001142801.2	c.977G>A	p.Ser326Asn	missense_variant	6/12		NP_001136273.1
EYS	NM_198283.2	c.977G>A	p.Ser326Asn	missense_variant	5/10		NP_938024.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.977G>A	p.Ser326Asn	missense_variant	6/43	5	NM_001142800.2	ENSP00000424243	A2
EYS	ENST00000370621.7	c.977G>A	p.Ser326Asn	missense_variant	6/44	1		ENSP00000359655	P2
EYS	ENST00000393380.6	c.977G>A	p.Ser326Asn	missense_variant	6/12	1		ENSP00000377042
EYS	ENST00000342421.9	c.977G>A	p.Ser326Asn	missense_variant	4/9	1		ENSP00000341818

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 541 AN: 151844 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00812

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00454

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00177 AC: 445 AN: 250760 Hom.: 0 AF XY: 0.00165 AC XY: 224 AN XY: 135540

Gnomad AFR exome AF: 0.00818

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.00556

GnomAD4 exome AF: 0.00132 AC: 1926 AN: 1461240 Hom.: 7 Cov.: 31 AF XY: 0.00131 AC XY: 952 AN XY: 726932

Gnomad4 AFR exome AF: 0.00757

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.000919

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00355 AC: 540 AN: 151962 Hom.: 2 Cov.: 32 AF XY: 0.00349 AC XY: 259 AN XY: 74282

Gnomad4 AFR AF: 0.00810

Gnomad4 AMR AF: 0.00453

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00163 Hom.: 0

Bravo AF: 0.00406

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00185 AC: 224

Asia WGS AF: 0.000868 AC: 3 AN: 3472

EpiCase AF: 0.00186

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Uncertain significance, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	EYS: BP4 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 32581362, 28041643) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Retinal dystrophy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 15, 2018	- -

Retinitis pigmentosa 25 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 18, 2017	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 13, 2023	Variant summary: EYS c.977G>A (p.Ser326Asn) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 250760 control chromosomes, predominantly at a frequency of 0.0082 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in EYS causing Retinitis Pigmentosa phenotype (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.977G>A has been reported in the literature in individuals affected with Retinitis Pigmentosa (Audo_2010, Wang_2014, El Shamieh_2015, Dieiro_2020). These reports do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20333770, 32483926, 25692139, 32581362, 25097241). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as likely pathogenic (n=1), uncertain significance (n=5), likely benign (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Autosomal recessive retinitis pigmentosa Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 17, 2020

- -

EYS-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.30
DANN	Benign	0.87
DEOGEN2	Benign	0.032	.;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.39	T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0069	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.045	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.030	N;N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.020	D;D;T;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.0010	B;.;.;B
Vest4		0.16
MVP		0.27
MPC		0.0098
ClinPred		0.0011	T
GERP RS		-1.7
Varity_R		0.054
gMVP		0.13

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: rs112822256; hg19: chr6-66115146;