2-181604091-A-T

Variant names:

• chr2-181604091-A-T
• rs6433923
• NM_201548.5:c.239-12T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201548.5(CERKL):​c.239-12T>A variant causes a 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 intron
• Scores: Splicing: ADA: 0.0001000
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0670
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• CERKL-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 26

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 166848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CERKL	NM_201548.5	c.239-12T>A		intron_variant	Intron 1 of 12	ENST00000410087.8	NP_963842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERKL	ENST00000410087.8	c.239-12T>A		intron_variant	Intron 1 of 12	1	NM_201548.5	ENSP00000386725.3

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

GnomAD2 exomes AF: 0.138 AC: 33265 AN: 240622 AF XY: 0.129

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 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

African (AFR) AF: 0.588 AC: 18361 AN: 31232

American (AMR) AF: 0.193 AC: 8529 AN: 44218

Ashkenazi Jewish (ASJ) AF: 0.0762 AC: 1969 AN: 25834

East Asian (EAS) AF: 0.112 AC: 4405 AN: 39162

South Asian (SAS) AF: 0.122 AC: 10362 AN: 85140

European-Finnish (FIN) AF: 0.117 AC: 6136 AN: 52258

Middle Eastern (MID) AF: 0.146 AC: 802 AN: 5508

European-Non Finnish (NFE) AF: 0.0744 AC: 80554 AN: 1082658

Other (OTH) AF: 0.119 AC: 7001 AN: 59016

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

African (AFR) AF: 0.573 AC: 23701 AN: 41398

American (AMR) AF: 0.187 AC: 2853 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0764 AC: 265 AN: 3470

East Asian (EAS) AF: 0.119 AC: 615 AN: 5182

South Asian (SAS) AF: 0.115 AC: 556 AN: 4822

European-Finnish (FIN) AF: 0.120 AC: 1273 AN: 10602

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0797 AC: 5422 AN: 68016

Other (OTH) AF: 0.187 AC: 396 AN: 2116

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.067
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6433923; hg19: chr2-182468818;