2-181604091-A-T

Position:

• chr2-181604091-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.239-12T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,577,114 control chromosomes in the GnomAD database, including 19,076 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (7598 hom., cov: 32)
  • Exomes 𝑓: 0.097 (11478 hom.)
• Consequence: CERKL NM_201548.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001000
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0670

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=-0.92).
• BP6: Variant 2-181604091-A-T is Benign according to our data. Variant chr2-181604091-A-T is described in ClinVar as [Benign]. Clinvar id is 166848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-181604091-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CERKL	NM_201548.5	c.239-12T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000410087.8	NP_963842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CERKL	ENST00000410087.8	c.239-12T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_201548.5	ENSP00000386725	P1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35085 AN: 151970 Hom.: 7579 Cov.: 32

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.0341

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.0764

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0797

Gnomad OTH AF: 0.189

GnomAD3 exomes AF: 0.138 AC: 33265 AN: 240622 Hom.: 3996 AF XY: 0.129 AC XY: 16942 AN XY: 130974

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.0789

Gnomad EAS exome AF: 0.123

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0810

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.0969 AC: 138119 AN: 1425026 Hom.: 11478 Cov.: 28 AF XY: 0.0969 AC XY: 68870 AN XY: 710698

Gnomad4 AFR exome AF: 0.588

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.0762

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.122

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.0744

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.231 AC: 35150 AN: 152088 Hom.: 7598 Cov.: 32 AF XY: 0.230 AC XY: 17095 AN XY: 74354

Gnomad4 AFR AF: 0.573

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.0764

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.0797

Gnomad4 OTH AF: 0.187

Alfa AF: 0.0658 Hom.: 123

Bravo AF: 0.254

Asia WGS AF: 0.128 AC: 447 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Retinitis pigmentosa 26 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

not provided Benign:2

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

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	-0.92
CADD	Benign	5.3
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.036
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: rs6433923; hg19: chr2-182468818;