rs17411795

Variant names:

• chr6-65295964-T-A
• rs17411795
• NM_001142800.2:c.1922A>T

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.1922A>T​(p.Glu641Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,551,002 control chromosomes in the GnomAD database, including 31,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E641E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2384 hom., cov: 33)
  • Exomes 𝑓: 0.20 (29597 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.425
• Publications: 21 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.004574895).
• BP6: Variant 6-65295964-T-A is Benign according to our data. Variant chr6-65295964-T-A is described in ClinVar as Benign. ClinVar VariationId is 137268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 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.1922A>T	p.Glu641Val	missense	Exon 12 of 43	NP_001136272.1	Q5T1H1-1
	EYS	NM_001292009.2		c.1922A>T	p.Glu641Val	missense	Exon 12 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.1922A>T	p.Glu641Val	missense	Exon 12 of 43	ENSP00000424243.1	Q5T1H1-1
	EYS	ENST00000370621.7	TSL:1	c.1922A>T	p.Glu641Val	missense	Exon 12 of 44	ENSP00000359655.3	Q5T1H1-3
	EYS	ENST00000370615.3	TSL:3	n.360A>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24611 AN: 151796 Hom.: 2385 Cov.: 33

Gnomad AFR AF: 0.0749

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.0583

Gnomad SAS AF: 0.0884

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.142

GnomAD2 exomes AF: 0.168 AC: 26497 AN: 157354 AF XY: 0.165

Gnomad AFR exome AF: 0.0660

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.207

Gnomad EAS exome AF: 0.0483

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.200 AC: 279555 AN: 1399088 Hom.: 29597 Cov.: 45 AF XY: 0.197 AC XY: 135724 AN XY: 690048

African (AFR) AF: 0.0662 AC: 2091 AN: 31580

American (AMR) AF: 0.123 AC: 4402 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 5303 AN: 25158

East Asian (EAS) AF: 0.0739 AC: 2642 AN: 35728

South Asian (SAS) AF: 0.0889 AC: 7046 AN: 79218

European-Finnish (FIN) AF: 0.281 AC: 13859 AN: 49364

Middle Eastern (MID) AF: 0.142 AC: 809 AN: 5700

European-Non Finnish (NFE) AF: 0.216 AC: 232876 AN: 1078594

Other (OTH) AF: 0.181 AC: 10527 AN: 58042

GnomAD4 genome AF: 0.162 AC: 24611 AN: 151914 Hom.: 2384 Cov.: 33 AF XY: 0.161 AC XY: 11970 AN XY: 74268

African (AFR) AF: 0.0748 AC: 3102 AN: 41476

American (AMR) AF: 0.134 AC: 2036 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 683 AN: 3470

East Asian (EAS) AF: 0.0581 AC: 300 AN: 5164

South Asian (SAS) AF: 0.0885 AC: 427 AN: 4826

European-Finnish (FIN) AF: 0.276 AC: 2919 AN: 10562

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14694 AN: 67864

Other (OTH) AF: 0.140 AC: 295 AN: 2108

Alfa AF: 0.202 Hom.: 2403

Bravo AF: 0.148

TwinsUK AF: 0.217 AC: 806

ALSPAC AF: 0.215 AC: 829

ESP6500AA AF: 0.0824 AC: 114

ESP6500EA AF: 0.209 AC: 666

ExAC AF: 0.153 AC: 3841

Asia WGS AF: 0.0750 AC: 262 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		0.42
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.30
MPC		0.057
ClinPred		0.053	T
GERP RS		0.45
Varity_R		0.20
gMVP		0.77
Mutation Taster		=91/9	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: rs17411795; hg19: chr6-66005857; COSMIC: COSV65458880;