rs12663622

Variant names:

• chr6-64591894-G-C
• rs12663622
• NM_001142800.2:c.3973C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-64591894-G-C
• chr6-64591894-G-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.3973C>G​(p.Gln1325Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,547,756 control chromosomes in the GnomAD database, including 13,776 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. Q1325K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.10 (924 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12852 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.11
• Publications: 14 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=0.0019658804).
• BP6: Variant 6-64591894-G-C is Benign according to our data. Variant chr6-64591894-G-C is described in ClinVar as Benign. ClinVar VariationId is 93608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.156 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.3973C>G	p.Gln1325Glu	missense	Exon 26 of 43	NP_001136272.1	Q5T1H1-1
	EYS	NM_001292009.2		c.3973C>G	p.Gln1325Glu	missense	Exon 26 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.3973C>G	p.Gln1325Glu	missense	Exon 26 of 43	ENSP00000424243.1	Q5T1H1-1
	EYS	ENST00000370621.7	TSL:1	c.3973C>G	p.Gln1325Glu	missense	Exon 26 of 44	ENSP00000359655.3	Q5T1H1-3

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15349 AN: 152054 Hom.: 926 Cov.: 32

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.0723

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0740

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.0989

GnomAD2 exomes AF: 0.117 AC: 17920 AN: 152598 AF XY: 0.118

Gnomad AFR exome AF: 0.0301

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.0803

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.0815

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.132 AC: 183552 AN: 1395584 Hom.: 12852 Cov.: 34 AF XY: 0.131 AC XY: 90292 AN XY: 688332

African (AFR) AF: 0.0299 AC: 943 AN: 31536

American (AMR) AF: 0.134 AC: 4758 AN: 35554

Ashkenazi Jewish (ASJ) AF: 0.0789 AC: 1980 AN: 25088

East Asian (EAS) AF: 0.144 AC: 5154 AN: 35696

South Asian (SAS) AF: 0.104 AC: 8184 AN: 78982

European-Finnish (FIN) AF: 0.0806 AC: 3971 AN: 49240

Middle Eastern (MID) AF: 0.0574 AC: 327 AN: 5692

European-Non Finnish (NFE) AF: 0.140 AC: 151077 AN: 1075924

Other (OTH) AF: 0.124 AC: 7158 AN: 57872

GnomAD4 genome AF: 0.101 AC: 15345 AN: 152172 Hom.: 924 Cov.: 32 AF XY: 0.0992 AC XY: 7380 AN XY: 74404

African (AFR) AF: 0.0363 AC: 1508 AN: 41530

American (AMR) AF: 0.124 AC: 1900 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 251 AN: 3472

East Asian (EAS) AF: 0.165 AC: 855 AN: 5168

South Asian (SAS) AF: 0.112 AC: 540 AN: 4816

European-Finnish (FIN) AF: 0.0740 AC: 786 AN: 10620

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9182 AN: 67976

Other (OTH) AF: 0.0979 AC: 207 AN: 2114

Alfa AF: 0.126 Hom.: 1005

Bravo AF: 0.105

TwinsUK AF: 0.135 AC: 500

ALSPAC AF: 0.128 AC: 494

ESP6500AA AF: 0.0354 AC: 49

ESP6500EA AF: 0.140 AC: 446

ExAC AF: 0.0969 AC: 2120

Asia WGS AF: 0.122 AC: 423 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	0.050
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.0010
DANN	Benign	0.11
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00052	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-1.1
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	0.089	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.0096
ClinPred		0.00044	T
GERP RS		-2.6
Varity_R		0.034
gMVP		0.057
Mutation Taster		=97/3	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: rs12663622; hg19: chr6-65301787; COSMIC: COSV58196646; COSMIC: COSV58196646;