NM_201548.5:c.895+3A>G

Variant names:

• chr2-181549631-T-C
• rs12623687
• NM_201548.5:c.895+3A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_201548.5(CERKL):​c.895+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,593,064 control chromosomes in the GnomAD database, including 13,141 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1568 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11573 hom.)
• Consequence: CERKL NM_201548.5 splice_region, intron
• Scores: Splicing: ADA: 0.9723
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.50
• Publications: 10 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 2-181549631-T-C is Benign according to our data. Variant chr2-181549631-T-C is described in ClinVar as Benign. ClinVar VariationId is 257151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERKL	NM_201548.5	c.895+3A>G		splice_region_variant, intron_variant	Intron 6 of 12	ENST00000410087.8	NP_963842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERKL	ENST00000410087.8	c.895+3A>G		splice_region_variant, intron_variant	Intron 6 of 12	1	NM_201548.5	ENSP00000386725.3

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20928 AN: 152056 Hom.: 1566 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.0672

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.0602

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.108

GnomAD2 exomes AF: 0.138 AC: 34509 AN: 250700 AF XY: 0.129

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.0664

Gnomad EAS exome AF: 0.214

Gnomad FIN exome AF: 0.211

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.120 AC: 172495 AN: 1440890 Hom.: 11573 Cov.: 27 AF XY: 0.117 AC XY: 83874 AN XY: 718166

African (AFR) AF: 0.145 AC: 4797 AN: 32984

American (AMR) AF: 0.207 AC: 9219 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.0626 AC: 1627 AN: 25970

East Asian (EAS) AF: 0.222 AC: 8753 AN: 39386

South Asian (SAS) AF: 0.0531 AC: 4560 AN: 85932

European-Finnish (FIN) AF: 0.211 AC: 11247 AN: 53378

Middle Eastern (MID) AF: 0.0577 AC: 329 AN: 5706

European-Non Finnish (NFE) AF: 0.114 AC: 124774 AN: 1093252

Other (OTH) AF: 0.120 AC: 7189 AN: 59664

GnomAD4 genome AF: 0.138 AC: 20954 AN: 152174 Hom.: 1568 Cov.: 32 AF XY: 0.143 AC XY: 10606 AN XY: 74398

African (AFR) AF: 0.150 AC: 6234 AN: 41524

American (AMR) AF: 0.173 AC: 2650 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0672 AC: 233 AN: 3468

East Asian (EAS) AF: 0.218 AC: 1128 AN: 5176

South Asian (SAS) AF: 0.0603 AC: 291 AN: 4826

European-Finnish (FIN) AF: 0.200 AC: 2115 AN: 10584

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8011 AN: 68000

Other (OTH) AF: 0.111 AC: 234 AN: 2112

Alfa AF: 0.123 Hom.: 736

Bravo AF: 0.137

Asia WGS AF: 0.169 AC: 586 AN: 3474

EpiCase AF: 0.107

EpiControl AF: 0.101

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Dec 09, 2016

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

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

Retinitis pigmentosa 26 Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 28, 2019

Mendelics

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	-0.23
CADD	Benign	22
DANN	Benign	0.97
PhyloP100		3.5
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.60
SpliceAI score (max)		0.090		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: rs12623687; hg19: chr2-182414358; COSMIC: COSV59212725;