rs2723341

Variant names:

• chr15-71811481-A-C
• rs2723341
• NM_014249.4:c.119-2A>C

Your query was ambiguous. Multiple possible variants found:

• chr15-71811481-A-C
• chr15-71811481-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_014249.4(NR2E3):​c.119-2A>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00066 in 1,555,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: NR2E3 NM_014249.4 splice_acceptor, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:37
• Conservation: PhyloP100: 4.05

Genes affected

NR2E3 (HGNC:7974): (nuclear receptor subfamily 2 group E member 3) This protein is part of a large family of nuclear receptor transcription factors involved in signaling pathways. Nuclear receptors have been shown to regulate pathways involved in embryonic development, as well as in maintenance of proper cell function in adults. Members of this family are characterized by discrete domains that function in DNA and ligand binding. This gene encodes a retinal nuclear receptor that is a ligand-dependent transcription factor. Defects in this gene are a cause of enhanced S cone syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 15-71811481-A-C is Pathogenic according to our data. Variant chr15-71811481-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-71811481-A-C is described in Lovd as [Pathogenic]. Variant chr15-71811481-A-C is described in Lovd as [Pathogenic]. Variant chr15-71811481-A-C is described in Lovd as [Likely_pathogenic]. Variant chr15-71811481-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2E3	NM_014249.4	c.119-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 7	ENST00000617575.5	NP_055064.1
NR2E3	NM_016346.4	c.119-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 6		NP_057430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2E3	ENST00000617575.5	c.119-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 7	1	NM_014249.4	ENSP00000482504.1
NR2E3	ENST00000621098.1	c.119-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 6	1		ENSP00000479962.1
NR2E3	ENST00000621736.4	c.-146-2A>C		splice_acceptor_variant, intron_variant	Intron 3 of 9	2		ENSP00000479254.1

Frequencies

GnomAD3 genomes AF: 0.000507 AC: 77 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000927

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000526 AC: 85 AN: 161472 Hom.: 0 AF XY: 0.000511 AC XY: 44 AN XY: 86034

Gnomad AFR exome AF: 0.000367

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000866

Gnomad FIN exome AF: 0.0000618

Gnomad NFE exome AF: 0.000990

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.000676 AC: 949 AN: 1402938 Hom.: 0 Cov.: 33 AF XY: 0.000683 AC XY: 473 AN XY: 692406

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.000111

Gnomad4 ASJ exome AF: 0.00131

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000629

Gnomad4 FIN exome AF: 0.0000404

Gnomad4 NFE exome AF: 0.000791

Gnomad4 OTH exome AF: 0.000688

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74380

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000927

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000615 Hom.: 0

Bravo AF: 0.000468

ExAC AF: 0.000192 AC: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:37

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:10

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 17, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 29, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25079116, 29343940, 32531858, 31725702, 32552793, 32581362, 10655056, 18294254, 19718767, 25097241, 24474277, 19273793, 21364904, 26894784, 27573156, 29193891, 28771251, 29431110, 28559085, 21686439, 31130284, 31980526, 30959774, 34426522, 31589614, 32679203, 32037395, 31816670, 31877679, 35113758, 31306293, 28224992, 30324420, 23591405, 31456290, 33138239, 21217109, 15459973) -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 1 of the NR2E3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NR2E3 are known to be pathogenic (PMID: 15459973, 27522502). This variant is present in population databases (rs2723341, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with autosomal recessive enhanced S-cone syndrome (PMID: 10655056, 24474277, 25079116). It has also been observed to segregate with disease in related individuals. This variant is also known as c.118-2A>C. ClinVar contains an entry for this variant (Variation ID: 191059). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18294254). For these reasons, this variant has been classified as Pathogenic. -

Apr 02, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NR2E3: PM3:Very Strong, PVS1, PM2, PS3:Supporting -

Enhanced S-cone syndrome Pathogenic:6

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2019

Hadassah Hebrew University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 19, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Retinitis pigmentosa 37 Pathogenic:5

Jan 03, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000191059, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000503, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The NR2E3 c.119-2A>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PM3. Based on this evidence we have classified this variant as Likely Pathogenic. -

Jun 10, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The NR2E3 variant (c.119-2A>C) identified in this patient is located in the -2 position of the splice acceptor site of intron 1 and segregated with retinitis pigmentosa in multiple families (Bandah et al. 2009, PMID 19273793; Haider et al. 2000, PMID 10655056; Beryozkin et al 2014, PMID 24474277; Wang et al 2014, PMID 25097241). Additionally, in vivo functional studies demonstrated altered splicing (PMID 18294254; Bernal et al 2008). -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1,PM2 -

Retinitis pigmentosa Pathogenic:3

Jul 24, 2023

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Clinical significance based on ACMG v2.0 -

Apr 01, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The c.119-2A>C variant in NR2E3 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37 Pathogenic:3

-

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2021

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_014249.2(NR2E3):c.119-2A>C is a canonical splice variant classified as pathogenic in the context of NR2E3-related disorders. c.119-2A>C has been observed in cases with relevant disease (PMID: 18294254, 15459973). Functional assessments of this variant are available in the literature (PMID: 18294254). c.119-2A>C has been observed in population frequency databases (gnomAD: NFE 0.1%). In summary, NM_014249.2(NR2E3):c.119-2A>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Mar 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:3

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

NR2E3-related disorder Pathogenic:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NR2E3 c.119-2A>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Across a selection of the available literature, the c.119-2A>C variant has been reported in 56 of 232 patients with NR2E3-related disorders, including 33 homozygotes and 23 compound heterozygotes. The variant is noted to segregate with disease (Schorderet et al. 2009; Collin et al. 2011; Yzer et al. 2013; Von Alpen et al. 2015). This variant was absent from 667 controls and is reported at a frequency of 0.00070 in the European (non-Finnish) population of the Exome Aggregation Consortium. Bernal et al. (2008) demonstrated that the c.119-2A>C variant resulted in aberrant splicing producing, in addition to the normal transcript, a transcript showing skipping of exon 2 and the generation of a premature stop codon in exon 3. Based on the evidence, the c.119-2A>C variant is classified as pathogenic for NR2E3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Inborn genetic diseases Pathogenic:1

Jul 16, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119-2A>C intronic variant results from a A to C substitution two nucleotides before coding exon 2 of the NR2E3 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the NR2E3 c.119-2A>C alteration was observed in 0.05% (97/192,798) of total alleles studied, with a frequency of 0.11% (10/8,884) in the Ashkenazi Jewish subpopulation. This alteration has been reported homozygous or compound heterozygous with a second variant in multiple unrelated patients with retinitis pigmentosa or enhanced S-cone syndrome (Haider, 2000; Bernal, 2008; Jespersgaard, 2019; De Carvalho, 2021). Expression of the c.119-2A>C mutant protein in COS7 cells and RT-PCR showed an abnormal transcript due to exon 2 skipping and the generation of a premature stop codon in exon 3 (Bernal, 2008). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -

Goldmann-Favre syndrome Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Pathogenic:1

May 05, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Color vision defect;C0271385:Horizontal nystagmus;C0854723:Retinal dystrophy;C3665347:Visual impairment Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy Pathogenic:1

Sep 01, 2016

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ocular albinism Pathogenic:1

Sep 09, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM3 very strong, PP1 strong -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Benign	0.94
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.76	D
GERP RS		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.95		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2723341; hg19: chr15-72103821;