2-181604076-T-G

Position:

chr2-181604076-T-G

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 257150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-181604076-T-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
CERKL	NM_201548.5 linkuse as main transcript	c.242A>C	p.Asp81Ala	missense_variant	2/13	ENST00000410087.8	NP_963842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CERKL	ENST00000410087.8 linkuse as main transcript	c.242A>C	p.Asp81Ala	missense_variant	2/13	1	NM_201548.5	ENSP00000386725	P1	Q49MI3-2

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

GnomAD3 exomes

AF:

0.148

AC:

36349

AN:

245128

Hom.:

3110

AF XY:

0.140

AC XY:

18591

AN XY:

133178

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 SAS exome

AF:

0.0587

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

Gnomad4 AFR exome

AF:

0.0959

Gnomad4 AMR exome

AF:

0.212

Gnomad4 ASJ exome

AF:

0.0715

Gnomad4 EAS exome

AF:

0.239

Gnomad4 SAS exome

AF:

0.0570

Gnomad4 FIN exome

AF:

0.230

Gnomad4 NFE exome

AF:

0.135

Gnomad4 OTH exome

AF:

0.134

GnomAD4 genome

AF:

0.137

AC:

20840

AN:

151986

Hom.:

1636

Cov.:

AF XY:

0.142

AC XY:

10572

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.107

Gnomad4 AMR

AF:

0.176

Gnomad4 ASJ

AF:

0.0778

Gnomad4 EAS

AF:

0.257

Gnomad4 SAS

AF:

0.0628

Gnomad4 FIN

AF:

0.217

Gnomad4 NFE

AF:

0.136

Gnomad4 OTH

AF:

0.120

Alfa

AF:

0.128

Hom.:

1498

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	GeneDx	Dec 09, 2016	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:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided

Benign:2

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

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

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

MutationTaster

Benign

1.0

P;P;P;P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over