rs9445051

Variant names:

• chr6-64626250-G-A
• rs9445051
• NM_001142800.2:c.3444-5C>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.3444-5C>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 0.228 in 1,512,526 control chromosomes in the GnomAD database, including 41,011 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3501 hom., cov: 31)
  • Exomes 𝑓: 0.23 (37510 hom.)
• Consequence: EYS NM_001142800.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002039
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.461
• Publications: 19 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-64626250-G-A is Benign according to our data. Variant chr6-64626250-G-A is described in ClinVar as Benign. ClinVar VariationId is 357717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2	c.3444-5C>T		splice_region_variant, intron_variant	Intron 22 of 42	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.3444-5C>T		splice_region_variant, intron_variant	Intron 22 of 43		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.3444-5C>T		splice_region_variant, intron_variant	Intron 22 of 42	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.3444-5C>T		splice_region_variant, intron_variant	Intron 22 of 43	1		ENSP00000359655.3
EYS	ENST00000330816.5	n.65-5C>T		splice_region_variant, intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29923 AN: 151602 Hom.: 3499 Cov.: 31

Gnomad AFR AF: 0.0709

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.311

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.247

GnomAD2 exomes AF: 0.225 AC: 27529 AN: 122246 AF XY: 0.225

Gnomad AFR exome AF: 0.0646

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.339

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.243

Gnomad OTH exome AF: 0.235

GnomAD4 exome AF: 0.231 AC: 314805 AN: 1360804 Hom.: 37510 Cov.: 29 AF XY: 0.230 AC XY: 154245 AN XY: 670310

African (AFR) AF: 0.0676 AC: 1964 AN: 29070

American (AMR) AF: 0.186 AC: 4603 AN: 24784

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 6267 AN: 24002

East Asian (EAS) AF: 0.319 AC: 11126 AN: 34906

South Asian (SAS) AF: 0.160 AC: 11314 AN: 70732

European-Finnish (FIN) AF: 0.251 AC: 12300 AN: 48964

Middle Eastern (MID) AF: 0.291 AC: 1615 AN: 5542

European-Non Finnish (NFE) AF: 0.237 AC: 252648 AN: 1066312

Other (OTH) AF: 0.230 AC: 12968 AN: 56492

GnomAD4 genome AF: 0.197 AC: 29924 AN: 151722 Hom.: 3501 Cov.: 31 AF XY: 0.198 AC XY: 14653 AN XY: 74114

African (AFR) AF: 0.0709 AC: 2934 AN: 41388

American (AMR) AF: 0.211 AC: 3225 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 885 AN: 3466

East Asian (EAS) AF: 0.339 AC: 1745 AN: 5150

South Asian (SAS) AF: 0.164 AC: 785 AN: 4792

European-Finnish (FIN) AF: 0.258 AC: 2695 AN: 10464

Middle Eastern (MID) AF: 0.315 AC: 92 AN: 292

European-Non Finnish (NFE) AF: 0.246 AC: 16710 AN: 67910

Other (OTH) AF: 0.246 AC: 516 AN: 2100

Alfa AF: 0.216 Hom.: 1808

Bravo AF: 0.190

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 25 Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Apr 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.71
PhyloP100		0.46
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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: rs9445051; hg19: chr6-65336143; COSMIC: COSV58203620; COSMIC: COSV58203620;