rs12997453

Positions:

• chr2-181548532-A-G
• chr2-181548532-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201548.5(CERKL):​c.1133+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,568,092 control chromosomes in the GnomAD database, including 276,784 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27050 hom., cov: 32)
  • Exomes 𝑓: 0.59 (249734 hom.)
• Consequence: CERKL NM_201548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.323

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-181548532-A-G is Benign according to our data. Variant chr2-181548532-A-G is described in ClinVar as [Benign]. Clinvar id is 257149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-181548532-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CERKL	NM_201548.5	c.1133+13T>C		intron_variant		ENST00000410087.8	NP_963842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CERKL	ENST00000410087.8	c.1133+13T>C		intron_variant		1	NM_201548.5	ENSP00000386725	P1

Frequencies

GnomAD3 genomes AF: 0.594 AC: 90208 AN: 151896 Hom.: 27035 Cov.: 32

Gnomad AFR AF: 0.608

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.632

Gnomad SAS AF: 0.830

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.618

GnomAD3 exomes AF: 0.610 AC: 149855 AN: 245500 Hom.: 46760 AF XY: 0.622 AC XY: 82465 AN XY: 132646

Gnomad AFR exome AF: 0.600

Gnomad AMR exome AF: 0.602

Gnomad ASJ exome AF: 0.602

Gnomad EAS exome AF: 0.633

Gnomad SAS exome AF: 0.834

Gnomad FIN exome AF: 0.484

Gnomad NFE exome AF: 0.575

Gnomad OTH exome AF: 0.607

GnomAD4 exome AF: 0.589 AC: 833933 AN: 1416078 Hom.: 249734 Cov.: 25 AF XY: 0.598 AC XY: 422966 AN XY: 707022

Gnomad4 AFR exome AF: 0.611

Gnomad4 AMR exome AF: 0.603

Gnomad4 ASJ exome AF: 0.611

Gnomad4 EAS exome AF: 0.616

Gnomad4 SAS exome AF: 0.836

Gnomad4 FIN exome AF: 0.489

Gnomad4 NFE exome AF: 0.570

Gnomad4 OTH exome AF: 0.598

GnomAD4 genome AF: 0.594 AC: 90278 AN: 152014 Hom.: 27050 Cov.: 32 AF XY: 0.596 AC XY: 44289 AN XY: 74306

Gnomad4 AFR AF: 0.608

Gnomad4 AMR AF: 0.613

Gnomad4 ASJ AF: 0.609

Gnomad4 EAS AF: 0.633

Gnomad4 SAS AF: 0.830

Gnomad4 FIN AF: 0.506

Gnomad4 NFE AF: 0.576

Gnomad4 OTH AF: 0.614

Alfa AF: 0.591 Hom.: 7307

Bravo AF: 0.596

Asia WGS AF: 0.680 AC: 2365 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Retinitis pigmentosa 26 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.7
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12997453; hg19: chr2-182413259; COSMIC: COSV59207851;