2-181604076-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_201548.5(CERKL):c.242A>C(p.Asp81Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,591,672 control chromosomes in the GnomAD database, including 16,562 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D81V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.14 ( 1636 hom., cov: 32)

Exomes 𝑓: 0.14 ( 14926 hom. )

Consequence

CERKL
NM_201548.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.95

Publications

19 publications found

Variant links:

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

CERKL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025988221).

BP6

Variant 2-181604076-T-G is Benign according to our data. Variant chr2-181604076-T-G is described in ClinVar as Benign. ClinVar VariationId is 257150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERKL	NM_201548.5 link	c.242A>C	p.Asp81Ala	missense_variant	Exon 2 of 13	ENST00000410087.8	NP_963842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERKL	ENST00000410087.8 link	c.242A>C	p.Asp81Ala	missense_variant	Exon 2 of 13	1	NM_201548.5	ENSP00000386725.3

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

20814

AN:

151868

Hom.:

1630

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.177

Gnomad ASJ

AF:

0.0778

Gnomad EAS

AF:

0.258

Gnomad SAS

AF:

0.0624

Gnomad FIN

AF:

0.217

Gnomad MID

AF:

0.0385

Gnomad NFE

AF:

0.136

Gnomad OTH

AF:

0.117

GnomAD2 exomes

AF:

0.148

AC:

36349

AN:

245128

AF XY:

0.140

show subpopulations

Gnomad AFR exome

AF:

0.106

Gnomad AMR exome

AF:

0.218

Gnomad ASJ exome

AF:

0.0708

Gnomad EAS exome

AF:

0.250

Gnomad FIN exome

AF:

0.228

Gnomad NFE exome

AF:

0.133

Gnomad OTH exome

AF:

0.141

GnomAD4 exome

AF:

0.137

AC:

197234

AN:

1439686

Hom.:

14926

Cov.:

AF XY:

0.134

AC XY:

95816

AN XY:

717346

show subpopulations

African (AFR)

AF:

0.0959

AC:

3096

AN:

32282

American (AMR)

AF:

0.212

AC:

9408

AN:

44318

Ashkenazi Jewish (ASJ)

AF:

0.0715

AC:

1853

AN:

25924

East Asian (EAS)

AF:

0.239

AC:

9403

AN:

39326

South Asian (SAS)

AF:

0.0570

AC:

4883

AN:

85704

European-Finnish (FIN)

AF:

0.230

AC:

12161

AN:

52794

Middle Eastern (MID)

AF:

0.0473

AC:

268

AN:

5660

European-Non Finnish (NFE)

AF:

0.135

AC:

148169

AN:

1094096

Other (OTH)

AF:

0.134

AC:

7993

AN:

59582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

7083

14166

21250

28333

35416

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5372

10744

16116

21488

26860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.137

AC:

20840

AN:

151986

Hom.:

1636

Cov.:

AF XY:

0.142

AC XY:

10572

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.107

AC:

4453

AN:

41472

American (AMR)

AF:

0.176

AC:

2690

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.0778

AC:

270

AN:

3472

East Asian (EAS)

AF:

0.257

AC:

1329

AN:

5174

South Asian (SAS)

AF:

0.0628

AC:

303

AN:

4822

European-Finnish (FIN)

AF:

0.217

AC:

2290

AN:

10536

Middle Eastern (MID)

AF:

0.0379

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.136

AC:

9215

AN:

67942

Other (OTH)

AF:

0.120

AC:

253

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

898

1796

2694

3592

4490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

232

464

696

928

1160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.129

Hom.:

2344

Bravo

AF:

0.134

TwinsUK

AF:

0.141

AC:

521

ALSPAC

AF:

0.136

AC:

523

ESP6500AA

AF:

0.112

AC:

492

ESP6500EA

AF:

0.128

AC:

1097

ExAC

AF:

0.140

AC:

16937

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Retinitis pigmentosa 26

Benign:2

Sep 16, 2020

Natera, Inc.

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

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Retinitis pigmentosa

Benign:1

Mar 06, 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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.043

.;.;.;T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.71

T;T;T;T;T

MetaRNN

Benign

0.0026

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L;L;L;L

PhyloP100

2.0

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.8

D;D;N;D;D

REVEL

Benign

0.12

Sift

Benign

0.16

T;T;D;T;T

Sift4G

Uncertain

0.019

D;D;D;D;D

Polyphen

0.78

P;.;P;P;P

Vest4

0.40

MPC

0.18

ClinPred

0.014

GERP RS

3.0

Varity_R

0.084

gMVP

0.38

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over