rs1553513437
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_201548.5(CERKL):c.1073+3_1073+6del variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,438 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
CERKL
NM_201548.5 splice_donor_5th_base, intron
NM_201548.5 splice_donor_5th_base, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.58
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 2-181548673-GACTT-G is Pathogenic according to our data. Variant chr2-181548673-GACTT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-181548673-GACTT-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CERKL | NM_201548.5 | c.1073+3_1073+6del | splice_donor_5th_base_variant, intron_variant | ENST00000410087.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CERKL | ENST00000410087.8 | c.1073+3_1073+6del | splice_donor_5th_base_variant, intron_variant | 1 | NM_201548.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461438Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727054
GnomAD4 exome
AF:
AC:
4
AN:
1461438
Hom.:
AF XY:
AC XY:
3
AN XY:
727054
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis pigmentosa 26 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 27, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 25, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 01, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 04, 2018 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change falls in intron 8 of the CERKL gene. It does not directly change the encoded amino acid sequence of the CERKL protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with retinal dystrophy (PMID: 27874104, 28041643). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1133+3_1133+6delAAGT. ClinVar contains an entry for this variant (Variation ID: 438052). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Autosomal recessive retinitis pigmentosa Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Faculty of Health Sciences, Beirut Arab University | Nov 22, 2016 | - - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 24
DS_DL_spliceai
Position offset: 7
Find out detailed SpliceAI scores and Pangolin per-transcript scores at