rs398122962

Positions:

• chr2-181603897-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_201548.5(CERKL):​c.420del​(p.Ile141LeufsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L140L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CERKL NM_201548.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: -0.230

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 2-181603897-TA-T is Pathogenic according to our data. Variant chr2-181603897-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91392.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CERKL	NM_201548.5	c.420del	p.Ile141LeufsTer3	frameshift_variant	2/13	ENST00000410087.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CERKL	ENST00000410087.8	c.420del	p.Ile141LeufsTer3	frameshift_variant	2/13	1	NM_201548.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa 26 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 04, 2022	The heterozygous p.Ile141LeufsTer3 variant in CERKL was identified by our study, along with a pathogenic variant, in 1 individual with retinitis pigmentosa 26. The variant has been reported in one European individual with retinitis pigmentosa 26 (PMID: 24043777), but was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 91392) as pathogenic by OMIM. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 141 and leads to a premature termination codon 3 amino acids downstream. This alteration is then 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 combination with a reported pathogenic variant and in 1 individual with retinitis pigmentosa 26 increases the likelihood that the p.Ile141LeufsTer3 variant is pathogenic (Variation ID: 2364; PMID: 24043777). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_strong, PM2, PM3 (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2013	- -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

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

Apr 01, 2021

The p.Ile141LeufsTer3 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/). Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Computational scores

Source: dbNSFP v4.3

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: rs398122962; hg19: chr2-182468624;