chr6-65353453-G-A

Variant names:

• chr6-65353453-G-A
• rs200387978
• NM_001142800.2:c.1459+5C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001142800.2(EYS):​c.1459+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000739 in 1,612,322 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (1 hom.)
• Consequence: EYS NM_001142800.2 splice_region, intron
• Scores: Splicing: ADA: 0.0004736
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:6
• Conservation: PhyloP100: -0.270
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

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.1459+5C>T		splice_region intron	N/A	NP_001136272.1	Q5T1H1-1
	EYS	NM_001292009.2		c.1459+5C>T		splice_region intron	N/A	NP_001278938.1	Q5T1H1-3
	EYS	NM_001142801.2		c.1459+5C>T		splice_region intron	N/A	NP_001136273.1	Q5T1H1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	ENST00000503581.6	TSL:5 MANE Select	c.1459+5C>T		splice_region intron	N/A	ENSP00000424243.1	Q5T1H1-1
	EYS	ENST00000370621.7	TSL:1	c.1459+5C>T		splice_region intron	N/A	ENSP00000359655.3	Q5T1H1-3
	EYS	ENST00000393380.6	TSL:1	c.1459+5C>T		splice_region intron	N/A	ENSP00000377042.2	Q5T1H1-4

Frequencies

GnomAD3 genomes AF: 0.000579 AC: 88 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000495 AC: 124 AN: 250482 AF XY: 0.000451

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000972

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000756 AC: 1104 AN: 1460186 Hom.: 1 Cov.: 31 AF XY: 0.000742 AC XY: 539 AN XY: 726426

African (AFR) AF: 0.000180 AC: 6 AN: 33420

American (AMR) AF: 0.000201 AC: 9 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39466

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53354

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 0.000942 AC: 1046 AN: 1110936

Other (OTH) AF: 0.000348 AC: 21 AN: 60308

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74362

African (AFR) AF: 0.000168 AC: 7 AN: 41544

American (AMR) AF: 0.000328 AC: 5 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000821 Hom.: 0

Bravo AF: 0.000480

EpiCase AF: 0.000547

EpiControl AF: 0.000594

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	2	-	Retinitis pigmentosa (2)
-	1	-	not specified (1)
-	1	-	Retinitis pigmentosa 25 (1)
1	-	-	Stargardt disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.1
DANN	Benign	0.26
PhyloP100		-0.27
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.028
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: rs200387978; hg19: chr6-66063346;