rs4710457

Variant names:

• chr6-63984461-C-T
• rs4710457
• NM_001142800.2:c.6977G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001142800.2(EYS):​c.6977G>A​(p.Arg2326Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,548,378 control chromosomes in the GnomAD database, including 99,961 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9478 hom., cov: 31)
  • Exomes 𝑓: 0.36 (90483 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0350
• Publications: 31 publications found

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]

EYS Gene-Disease associations (from GenCC):

• EYS-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• retinitis pigmentosa 25

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

LOC107986608 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9803643E-4).
• BP6: Variant 6-63984461-C-T is Benign according to our data. Variant chr6-63984461-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142800.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	NM_001142800.2	MANE Select	c.6977G>A	p.Arg2326Gln	missense	Exon 35 of 43	NP_001136272.1
	EYS	NM_001292009.2		c.6977G>A	p.Arg2326Gln	missense	Exon 35 of 44	NP_001278938.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	ENST00000503581.6	TSL:5 MANE Select	c.6977G>A	p.Arg2326Gln	missense	Exon 35 of 43	ENSP00000424243.1
	EYS	ENST00000370621.7	TSL:1	c.6977G>A	p.Arg2326Gln	missense	Exon 35 of 44	ENSP00000359655.3
	EYS	ENST00000398580.3	TSL:5	c.290G>A	p.Arg97Gln	missense	Exon 3 of 10	ENSP00000381585.3

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53322 AN: 151316 Hom.: 9479 Cov.: 31

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.373

GnomAD2 exomes AF: 0.335 AC: 52628 AN: 156904 AF XY: 0.344

Gnomad AFR exome AF: 0.378

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.353

Gnomad FIN exome AF: 0.297

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.358 AC: 499678 AN: 1396944 Hom.: 90483 Cov.: 34 AF XY: 0.359 AC XY: 247255 AN XY: 689104

African (AFR) AF: 0.385 AC: 12109 AN: 31436

American (AMR) AF: 0.230 AC: 8191 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 9356 AN: 25106

East Asian (EAS) AF: 0.349 AC: 12447 AN: 35708

South Asian (SAS) AF: 0.382 AC: 30259 AN: 79198

European-Finnish (FIN) AF: 0.300 AC: 14781 AN: 49294

Middle Eastern (MID) AF: 0.358 AC: 2030 AN: 5674

European-Non Finnish (NFE) AF: 0.361 AC: 389318 AN: 1076962

Other (OTH) AF: 0.366 AC: 21187 AN: 57888

GnomAD4 genome AF: 0.352 AC: 53346 AN: 151434 Hom.: 9478 Cov.: 31 AF XY: 0.347 AC XY: 25632 AN XY: 73952

African (AFR) AF: 0.380 AC: 15686 AN: 41332

American (AMR) AF: 0.277 AC: 4207 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1274 AN: 3456

East Asian (EAS) AF: 0.335 AC: 1705 AN: 5092

South Asian (SAS) AF: 0.379 AC: 1825 AN: 4816

European-Finnish (FIN) AF: 0.288 AC: 3047 AN: 10562

Middle Eastern (MID) AF: 0.366 AC: 107 AN: 292

European-Non Finnish (NFE) AF: 0.357 AC: 24187 AN: 67680

Other (OTH) AF: 0.368 AC: 774 AN: 2104

Alfa AF: 0.361 Hom.: 21940

Bravo AF: 0.353

TwinsUK AF: 0.366 AC: 1356

ALSPAC AF: 0.371 AC: 1431

ESP6500AA AF: 0.384 AC: 531

ESP6500EA AF: 0.351 AC: 1118

ExAC AF: 0.346 AC: 8550

Asia WGS AF: 0.342 AC: 1188 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Retinitis pigmentosa 25 (3)
-	-	2	Retinitis pigmentosa (2)
-	-	1	not provided (1)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.00020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.035
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.11
Sift	Benign	0.065	T
Sift4G	Uncertain	0.027	D
Polyphen		0.010	B
Vest4		0.098
MPC		0.015
ClinPred		0.0035	T
GERP RS		0.33
Varity_R		0.025
gMVP		0.75
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4710457; hg19: chr6-64694354; COSMIC: COSV65460522;