rs9294631

Variant names:

• chr6-64912570-A-G
• rs9294631
• NM_001142800.2:c.2555T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-64912570-A-G
• chr6-64912570-A-C

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.2555T>C​(p.Leu852Pro) variant causes a missense change. The variant allele was found at a frequency of 0.593 in 1,550,694 control chromosomes in the GnomAD database, including 276,892 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L852A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.66 (34884 hom., cov: 32)
  • Exomes 𝑓: 0.59 (242008 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.23
• Publications: 39 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ENSG00000308351 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=3.853312E-6).
• BP6: Variant 6-64912570-A-G is Benign according to our data. Variant chr6-64912570-A-G is described in ClinVar as Benign. ClinVar VariationId is 93605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.864 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	NM_001142800.2	MANE Select	c.2555T>C	p.Leu852Pro	missense	Exon 16 of 43	NP_001136272.1	Q5T1H1-1
	EYS	NM_001292009.2		c.2555T>C	p.Leu852Pro	missense	Exon 16 of 44	NP_001278938.1	Q5T1H1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	ENST00000503581.6	TSL:5 MANE Select	c.2555T>C	p.Leu852Pro	missense	Exon 16 of 43	ENSP00000424243.1	Q5T1H1-1
	EYS	ENST00000370621.7	TSL:1	c.2555T>C	p.Leu852Pro	missense	Exon 16 of 44	ENSP00000359655.3	Q5T1H1-3
	ENSG00000308351	ENST00000833459.1		n.173-3753A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.664 AC: 100789 AN: 151842 Hom.: 34846 Cov.: 32

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.654

GnomAD2 exomes AF: 0.593 AC: 92797 AN: 156496 AF XY: 0.586

Gnomad AFR exome AF: 0.882

Gnomad AMR exome AF: 0.619

Gnomad ASJ exome AF: 0.695

Gnomad EAS exome AF: 0.402

Gnomad FIN exome AF: 0.580

Gnomad NFE exome AF: 0.580

Gnomad OTH exome AF: 0.612

GnomAD4 exome AF: 0.585 AC: 818369 AN: 1398734 Hom.: 242008 Cov.: 42 AF XY: 0.583 AC XY: 402451 AN XY: 689884

African (AFR) AF: 0.887 AC: 28006 AN: 31578

American (AMR) AF: 0.626 AC: 22335 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 17452 AN: 25170

East Asian (EAS) AF: 0.437 AC: 15592 AN: 35718

South Asian (SAS) AF: 0.562 AC: 44528 AN: 79208

European-Finnish (FIN) AF: 0.579 AC: 28540 AN: 49276

Middle Eastern (MID) AF: 0.647 AC: 3689 AN: 5698

European-Non Finnish (NFE) AF: 0.578 AC: 623169 AN: 1078404

Other (OTH) AF: 0.605 AC: 35058 AN: 57978

GnomAD4 genome AF: 0.664 AC: 100881 AN: 151960 Hom.: 34884 Cov.: 32 AF XY: 0.660 AC XY: 49037 AN XY: 74258

African (AFR) AF: 0.871 AC: 36149 AN: 41484

American (AMR) AF: 0.641 AC: 9769 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2426 AN: 3472

East Asian (EAS) AF: 0.408 AC: 2107 AN: 5170

South Asian (SAS) AF: 0.554 AC: 2665 AN: 4810

European-Finnish (FIN) AF: 0.577 AC: 6094 AN: 10568

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39600 AN: 67896

Other (OTH) AF: 0.655 AC: 1384 AN: 2112

Alfa AF: 0.612 Hom.: 82135

Bravo AF: 0.675

TwinsUK AF: 0.586 AC: 2172

ALSPAC AF: 0.568 AC: 2189

ESP6500AA AF: 0.878 AC: 1215

ESP6500EA AF: 0.575 AC: 1831

ExAC AF: 0.595 AC: 14197

Asia WGS AF: 0.556 AC: 1934 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Retinitis pigmentosa 25 (5)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Retinitis pigmentosa (2)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.080
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0000039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.56	N
PhyloP100		4.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	4.3	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.059
MPC		0.0093
ClinPred		0.0061	T
GERP RS		3.1
Varity_R		0.047
gMVP		0.93
Mutation Taster		=90/10	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: rs9294631; hg19: chr6-65622463; COSMIC: COSV65505165;