NM_001142800.2:c.1300-3C>T

Variant names:

• chr6-65353620-G-A
• rs1936439
• NM_001142800.2:c.1300-3C>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.1300-3C>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 0.678 in 1,606,356 control chromosomes in the GnomAD database, including 370,343 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 0.67 (34623 hom., cov: 31)
  • Exomes 𝑓: 0.68 (335720 hom.)
• Consequence: EYS NM_001142800.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001210
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.199
• Publications: 15 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=-0.91).
• BP6: Variant 6-65353620-G-A is Benign according to our data. Variant chr6-65353620-G-A is described in ClinVar as Benign. ClinVar VariationId is 137263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2	c.1300-3C>T		splice_region_variant, intron_variant	Intron 8 of 42	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.1300-3C>T		splice_region_variant, intron_variant	Intron 8 of 43		NP_001278938.1
EYS	NM_001142801.2	c.1300-3C>T		splice_region_variant, intron_variant	Intron 8 of 11		NP_001136273.1
EYS	NM_198283.2	c.1300-3C>T		splice_region_variant, intron_variant	Intron 7 of 9		NP_938024.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.1300-3C>T		splice_region_variant, intron_variant	Intron 8 of 42	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.1300-3C>T		splice_region_variant, intron_variant	Intron 8 of 43	1		ENSP00000359655.3
EYS	ENST00000393380.6	c.1300-3C>T		splice_region_variant, intron_variant	Intron 8 of 11	1		ENSP00000377042.2
EYS	ENST00000342421.9	c.1300-3C>T		splice_region_variant, intron_variant	Intron 6 of 8	1		ENSP00000341818.5

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102361 AN: 151758 Hom.: 34610 Cov.: 31

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.609

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.601

Gnomad SAS AF: 0.712

Gnomad FIN AF: 0.683

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.647

GnomAD2 exomes AF: 0.671 AC: 168175 AN: 250504 AF XY: 0.675

Gnomad AFR exome AF: 0.684

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.683

Gnomad EAS exome AF: 0.600

Gnomad FIN exome AF: 0.679

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.665

GnomAD4 exome AF: 0.678 AC: 986330 AN: 1454480 Hom.: 335720 Cov.: 33 AF XY: 0.680 AC XY: 492000 AN XY: 723924

African (AFR) AF: 0.689 AC: 22954 AN: 33318

American (AMR) AF: 0.622 AC: 27767 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 18018 AN: 26068

East Asian (EAS) AF: 0.585 AC: 23105 AN: 39464

South Asian (SAS) AF: 0.715 AC: 61443 AN: 85980

European-Finnish (FIN) AF: 0.679 AC: 36223 AN: 53358

Middle Eastern (MID) AF: 0.656 AC: 3772 AN: 5750

European-Non Finnish (NFE) AF: 0.681 AC: 752761 AN: 1105756

Other (OTH) AF: 0.670 AC: 40287 AN: 60122

GnomAD4 genome AF: 0.674 AC: 102414 AN: 151876 Hom.: 34623 Cov.: 31 AF XY: 0.672 AC XY: 49883 AN XY: 74210

African (AFR) AF: 0.690 AC: 28573 AN: 41440

American (AMR) AF: 0.609 AC: 9266 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 2440 AN: 3464

East Asian (EAS) AF: 0.601 AC: 3092 AN: 5148

South Asian (SAS) AF: 0.713 AC: 3436 AN: 4822

European-Finnish (FIN) AF: 0.683 AC: 7210 AN: 10562

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46423 AN: 67904

Other (OTH) AF: 0.648 AC: 1368 AN: 2112

Alfa AF: 0.682 Hom.: 23841

Bravo AF: 0.668

Asia WGS AF: 0.643 AC: 2231 AN: 3474

EpiCase AF: 0.685

EpiControl AF: 0.680

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 05, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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 25 Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Benign:2

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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.80
DANN	Benign	0.21
PhyloP100		-0.20
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.032
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: rs1936439; hg19: chr6-66063513; COSMIC: COSV60980308;