6-64590357-C-G

Position:

• chr6-64590357-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001142800.2(EYS):​c.5510G>C​(p.Trp1837Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,551,246 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.0033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (24 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.444

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049631596).
• BP6: Variant 6-64590357-C-G is Benign according to our data. Variant chr6-64590357-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195937.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=2}. Variant chr6-64590357-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYS	NM_001142800.2	c.5510G>C	p.Trp1837Ser	missense_variant	26/43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.5510G>C	p.Trp1837Ser	missense_variant	26/44		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.5510G>C	p.Trp1837Ser	missense_variant	26/43	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.5510G>C	p.Trp1837Ser	missense_variant	26/44	1		ENSP00000359655.3

Frequencies

GnomAD3 genomes AF: 0.00326 AC: 496 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00444

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00399 AC: 614 AN: 153716 Hom.: 6 AF XY: 0.00397 AC XY: 324 AN XY: 81536

Gnomad AFR exome AF: 0.000506

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.000262

Gnomad NFE exome AF: 0.00497

Gnomad OTH exome AF: 0.00370

GnomAD4 exome AF: 0.00419 AC: 5869 AN: 1399056 Hom.: 24 Cov.: 33 AF XY: 0.00420 AC XY: 2899 AN XY: 690034

Gnomad4 AFR exome AF: 0.000728

Gnomad4 AMR exome AF: 0.00294

Gnomad4 ASJ exome AF: 0.0284

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.000223

Gnomad4 NFE exome AF: 0.00436

Gnomad4 OTH exome AF: 0.00459

GnomAD4 genome AF: 0.00326 AC: 496 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.00297 AC XY: 221 AN XY: 74406

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00444

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00633 Hom.: 7

Bravo AF: 0.00357

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00145 AC: 2

ESP6500EA AF: 0.00283 AC: 9

ExAC AF: 0.00439 AC: 96

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24265693) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	EYS: BP4, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2022	Variant summary: EYS c.5510G>C (p.Trp1837Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 153716 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 1.17 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 benign. c.5510G>C has been reported in the literature in individuals affected with Retinitis Pigmentosa, however it is often observed in the heterozygous state without a variant reported in the second allele and in several studies the variant was considered to be a polymorphism (example Audo_2010, Eisenberger_2013, Wang_2014, Perez-Carro_2016). These reports do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa. Six ClinVar submitters have provided assessments for this variant after 2014. Two classified the variant as benign, three as likely benign, and one as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2014	- -

Retinitis pigmentosa 25 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 09, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.040	.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.75	N;N
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.39	T;T
Polyphen		0.98	D;P
Vest4		0.34
MVP		0.55
MPC		0.057
ClinPred		0.057	T
GERP RS		3.3
Varity_R		0.20
gMVP		0.032

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: rs199689193; hg19: chr6-65300250;