rs794727120

Variant names:

• chr6-64997647-G-A
• rs794727120
• NM_001142800.2:c.2194C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-64997647-G-A
• chr6-64997647-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001142800.2(EYS):​c.2194C>T​(p.Gln732*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000858 in 1,398,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: EYS NM_001142800.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.76
• Publications: 5 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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-64997647-G-A is Pathogenic according to our data. Variant chr6-64997647-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 194358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2194C>T	p.Gln732*	stop_gained	Exon 14 of 43	NP_001136272.1
	EYS	NM_001292009.2		c.2194C>T	p.Gln732*	stop_gained	Exon 14 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.2194C>T	p.Gln732*	stop_gained	Exon 14 of 43	ENSP00000424243.1
	EYS	ENST00000370621.7	TSL:1	c.2194C>T	p.Gln732*	stop_gained	Exon 14 of 44	ENSP00000359655.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000858 AC: 12 AN: 1398880 Hom.: 0 Cov.: 30 AF XY: 0.0000101 AC XY: 7 AN XY: 689972

African (AFR) AF: 0.00 AC: 0 AN: 31580

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.00 AC: 0 AN: 35680

South Asian (SAS) AF: 0.00 AC: 0 AN: 79220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1078516

Other (OTH) AF: 0.00 AC: 0 AN: 58002

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.077
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		1.8
Vest4		0.93
GERP RS		0.27
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs794727120; hg19: chr6-65707540; COSMIC: COSV65476766;