rs121909398

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_201548.5(CERKL):c.769C>T(p.Arg257Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000593 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 0 hom. )

Consequence

CERKL
NM_201548.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:33

Conservation

PhyloP100: -0.0780

Variant links:

Genes affected

CERKL (HGNC:21699): (ceramide kinase like) This gene was initially identified as a locus (RP26) associated with an autosomal recessive form of retinitis pigmentosa (arRP) disease. This gene encodes a protein with ceramide kinase-like domains, however, the protein does not phosphorylate ceramide and its target substrate is currently unknown. This protein may be a negative regulator of apoptosis in photoreceptor cells. Mutations in this gene cause a form of retinitis pigmentosa characterized by autosomal recessive cone and rod dystrophy (arCRD). Alternative splicing of this gene results in multiple transcript variants encoding different isoforms and non-coding transcripts.[provided by RefSeq, May 2010]

CERKL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-181558617-G-A is Pathogenic according to our data. Variant chr2-181558617-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-181558617-G-A is described in Lovd as [Pathogenic]. Variant chr2-181558617-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-181558617-G-A is described in Lovd as [Pathogenic]. Variant chr2-181558617-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CERKL	NM_201548.5 linkuse as main transcript	c.769C>T	p.Arg257Ter	stop_gained	5/13	ENST00000410087.8	NP_963842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CERKL	ENST00000410087.8 linkuse as main transcript	c.769C>T	p.Arg257Ter	stop_gained	5/13	1	NM_201548.5	ENSP00000386725	P1	Q49MI3-2

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000346

AC:

AN:

248832

Hom.:

AF XY:

0.000407

AC XY:

AN XY:

134974

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000550

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000616

AC:

900

AN:

1461512

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

459

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000603

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000708

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.000375

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000390

Hom.:

Bravo

AF:

0.000317

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000247

AC:

ESP6500EA

AF:

0.000599

AC:

ExAC

AF:

0.000397

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:33

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 26

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 22, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 04, 2022	The heterozygous p.Arg283Ter variant in CERKL (also referred to as p.Arg257Ter) was identified by our study, along with a likely pathogenic variant, in 1 individual with retinitis pigmentosa 26. The variant has been reported in at least 9 individuals of Danish, Spanish, and unknown ethnicity with retinitis pigmentosa 26 (PMID: 14681825, 25097241), segregated with disease in 6 affected relatives from 2 families (PMID: 14681825), and has been identified in 0.05% (62/112768) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121909398). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 2364) as pathogenic by multiple submitters and as likely pathogenic by Medical Genetics Laboratory, Kennedy Center, Juliane Marie Center, Rigshospitalet. This nonsense variant leads to a premature termination codon at position 283, which is predicted to lead to a truncated or absent protein. Loss of function of the CERKL gene is a moderately established disease mechanism in autosomal recessive retinitis pigmentosa 26. The presence of this variant in at least 8 affected homozygotes, in combination with at least 1 reported pathogenic variant, and in at least 9 individuals with retinitis pigmentosa 26 increases the likelihood that the p.Arg283Ter variant is pathogenic (Variation ID: 91393; PMID: 14681825, 25097241). In summary, this variant meets criteria to be classified as pathogenic for retinitis pigmentosa 26 in an autosomal recessive manner based on the predicted impact of the variant, segregation in multiple families, and multiple homozygous occurrences and occurrences with pathogenic CERKL variants in affected individuals. ACMG/AMP Criteria applied: PVS1_strong, PP1_strong, PM3_strong (Richards 2015). -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The CERKL c.847C>T 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: PVS1, PS3, PM2, PM3, PP1, PP5. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 08, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 17, 2022	- -

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CERKL: PM3:Very Strong, PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21151602, 29555955, 29068140, 30337596, 28157192, 15708351, 24123366, 25097241, 25525159, 14681825, 28041643, 25999674, 22164218, 24043777, 18515597, 30718709, 28559085, 31082679, 34426522, 32411380, 32036094, 32865075, 31456290, 32581362, 31589614, 33576794, 33322828, 31054281, 32037395) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 26, 2020	This sequence change creates a premature translational stop signal (p.Arg283) in the CERKL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121909398, ExAC 0.07%). This variant has been reported as compound heterozygous or homozygous in several individuals and families affected with retinitis pigmentosa, retinal dystrophy, and cone-rod dystrophy (PMID: 14681825, 21151602, 221642182, 24625443, 25097241, 28041643). This variant is also known as Arg257 in the literature. ClinVar contains an entry for this variant (Variation ID: 2364). Loss-of-function variants in CERKL are known to be pathogenic (PMID: 14681825, 24043777). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2016	- -

Retinitis pigmentosa

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 25, 2022	Variant summary: CERKL c.847C>T (p.Arg283X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Retinitis pigmentosa in HGMD and been classified as pathogenic in Clinvar. The variant allele was found at a frequency of 0.00035 in 248832 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CERKL causing Retinitis Pigmentosa (0.00035 vs 0.0013), allowing no conclusion about variant significance. c.847C>T has been reported in the literature in multiple families affected with Retinitis Pigmentosa, with strong segregation of the variant with disease (eg. Tuson_2004, Aleman_2009, Khan_2013, etc). These data indicate that the variant is very likely to be associated with disease. 22 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	The p.Arg283Ter variant in CERKL 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, PS3, PM2, PM3, PP1, PP5. 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. -
Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The CERKL c.769C>T (p.Arg257Ter) variant, also referred to as c.847C>T (p.Arg283Ter), is a stop-gained variant and is predicted to result in a premature termination of the protein. The p.Arg257Ter variant has been reported in at least five studies in which it is found in at least 24 individuals with retinitis pigmentosa including 21 in a homozygous state from 13 families, and three affected siblings from an additional family in a compound heterozygous state (Tuson et al. 2004; Avila-Fernandez et al. 2010; Gonzalez-del Pozo et al. 2011; Nishiguchi et al. 2013; van Huet et al. 2015). The variant was absent from 360 control individuals and is reported at a frequency of 0.00067 in the South Asian population of the Exome Aggregation Consortium. The variant is located in the conserved catalytic domain of the protein (Tuson et al. 2004) and is reported to segregate with disease in several families (Avila-Fernandez et al. 2010; Gonzalez-del Pozo et al. 2011). Due to the potential impact of stop-gained variants and the supporting evidence, the p.Arg257Ter variant is classified as pathogenic for recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	research	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	Jul 24, 2023	Clinical significance based on ACMG v2.0 -
Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Cone-rod dystrophy

Pathogenic:4

Pathogenic, criteria provided, single submitter	research	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	Jul 24, 2023	Clinical significance based on ACMG v2.0 -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -
Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Retinal dystrophy

Pathogenic:2

Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 02, 2019	- -

Cone dystrophy;C1840457:Retinal pigment epithelial atrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Aug 25, 2020

ACMG classification criteria: PVS1, PM3 -

CERKL-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

The CERKL c.847C>T variant is predicted to result in premature protein termination (p.Arg283*). This variant can also be denoted as c.769C>T (p.Arg257*) in transcript NM_201548.4. This variant has been reported many times to be causative for autosomal recessive retinitis pigmentosa (Tuson et al. 2004. PubMed ID: 14681825; Littink et al. 2010. PubMed ID: 20554613; Stone et al. 2017. PubMed ID: 28559085). This variant is reported in 0.054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in CERKL are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/2364/). Given the evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Benign

0.89

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.021

MutationTaster

Benign

1.0

A;A;A;N;N

Vest4

0.87

GERP RS

-11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over