rs45628235

chr6-65057741-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001142800.2(EYS):c.2024-14C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,402,738 control chromosomes in the GnomAD database, including 37,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3422 hom., cov: 31)
  • Exomes 𝑓: 0.22 (33657 hom.)
• Consequence: EYS NM_001142800.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.26

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-65057741-G-A is Benign according to our data. Variant chr6-65057741-G-A is described in ClinVar as [Benign]. Clinvar id is 137269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-65057741-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.2024-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000503581.6
EYS	NM_001292009.2	c.2024-14C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.2024-14C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.2024-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1		P2

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30444 AN: 150418 Hom.: 3420 Cov.: 31

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.0507

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.215

GnomAD3 exomes AF: 0.243 AC: 32726 AN: 134792 Hom.: 3989 AF XY: 0.251 AC XY: 18067 AN XY: 71846

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.149

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.0598

Gnomad SAS exome AF: 0.302

Gnomad FIN exome AF: 0.316

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.223 AC: 278888 AN: 1252202 Hom.: 33657 Cov.: 20 AF XY: 0.227 AC XY: 141772 AN XY: 624354

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.134

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.0419

Gnomad4 SAS exome AF: 0.268

Gnomad4 FIN exome AF: 0.308

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.202 AC: 30450 AN: 150536 Hom.: 3422 Cov.: 31 AF XY: 0.206 AC XY: 15123 AN XY: 73446

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.0510

Gnomad4 SAS AF: 0.258

Gnomad4 FIN AF: 0.316

Gnomad4 NFE AF: 0.247

Gnomad4 OTH AF: 0.217

Alfa AF: 0.234 Hom.: 802

Bravo AF: 0.181

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2011	The variant is found in ARRP panel(s). -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 17, 2023

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.92
Cadd	Benign	0.31
Dann	Benign	0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs45628235; hg19: chr6-65767634;