2-181604002-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong

The NM_201548.5(CERKL):​c.316C>A​(p.Arg106Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,612,490 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R106C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CERKL
NM_201548.5 missense

Scores

2
11
6

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.85
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-181604002-G-A is described in Lovd as [Pathogenic].
PP5
Variant 2-181604002-G-T is Pathogenic according to our data. Variant chr2-181604002-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-181604002-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CERKLNM_201548.5 linkc.316C>A p.Arg106Ser missense_variant Exon 2 of 13 ENST00000410087.8 NP_963842.1 Q49MI3-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CERKLENST00000410087.8 linkc.316C>A p.Arg106Ser missense_variant Exon 2 of 13 1 NM_201548.5 ENSP00000386725.3 Q49MI3-2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
151950
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000625
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000520
AC:
13
AN:
249812
Hom.:
0
AF XY:
0.0000740
AC XY:
10
AN XY:
135128
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000426
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000377
AC:
55
AN:
1460422
Hom.:
0
Cov.:
31
AF XY:
0.0000647
AC XY:
47
AN XY:
726524
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000615
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152068
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000626
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinitis pigmentosa 26 Pathogenic:5
Mar 27, 2024
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 31, 2022
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 26 (MIM#608380). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to serine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (highest allele: 16 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional nuclear localization signal sequence (KLKRR) (PMID: 19501188). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change to a cysteine has been reported in individuals with cone-rod dystrophy (ClinVar, PMID: 29068140). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with retinitis pigmentosa (ClinVar, PMID: 18978954, 34315337). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in a large Parkistani family (PMID: 18978954). (SP) 1002 - This variant has limited functional evidence supporting abnormal protein function. CERKL has been proven to modulate the oxidation of TRX2, a mitochondria-specific regulator of redox balance and apoptosis. In vitro studies using GST pull-down assay has shown that this variant significantly reduced the binding of CERKL and TRX2 (PMID: 24735978). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 16, 2020
Natera, Inc.
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 08, 2021
Ocular Genomics Institute, Massachusetts Eye and Ear
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

The CERKL c.316C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PP1, PM3, PM2, PM5. Based on this evidence we have classified this variant as Likely Pathogenic. -

Apr 02, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:2
Jun 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 106 of the CERKL protein (p.Arg106Ser). This variant is present in population databases (rs569826109, gnomAD 0.04%). This missense change has been observed in individuals with clinical features of inherited retinal dystrophy (PMID: 18978954; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438054). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg106 amino acid residue in CERKL. Other variant(s) that disrupt this residue have been observed in individuals with CERKL-related conditions (PMID: 28838317), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Nov 14, 2024
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18978954, 28041643, 24735978, 32411380, 19667359, 33322828, 34315337) -

Retinal dystrophy Pathogenic:1
Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Retinitis pigmentosa Pathogenic:1
Mar 30, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CERKL c.316C>A (p.Arg106Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 249812 control chromosomes, predominantly at a frequency of 0.00043 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CERKL causing Retinitis Pigmentosa (5.2e-05 vs 0.0013), allowing no conclusion about variant significance. c.316C>A has been reported in the literature as a biallelic genotype in multiple individuals affected with retinal dystrophies and was shown to segregate with disease in at least one family (e.g. Ali_2008, Downes_2020, Duzkale_2021). These data indicate that the variant is very likely to be associated with disease. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Five classified the variant as pathogenic (n=2)/likely pathogenic (n=3) and one classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.64
BayesDel_addAF
Uncertain
0.014
T
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.054
.;.;.;T;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D;D;D;D
M_CAP
Benign
0.027
D
MetaRNN
Uncertain
0.65
D;D;D;D;D
MetaSVM
Benign
-0.92
T
MutationAssessor
Uncertain
2.5
M;M;M;M;M
PrimateAI
Benign
0.48
T
PROVEAN
Uncertain
-3.5
D;D;D;D;D
REVEL
Uncertain
0.37
Sift
Benign
0.099
T;T;D;T;T
Sift4G
Uncertain
0.013
D;D;D;D;D
Polyphen
1.0
D;.;D;D;D
Vest4
0.81
MutPred
0.63
Loss of MoRF binding (P = 0.0266);Loss of MoRF binding (P = 0.0266);Loss of MoRF binding (P = 0.0266);Loss of MoRF binding (P = 0.0266);Loss of MoRF binding (P = 0.0266);
MVP
0.73
MPC
0.52
ClinPred
0.86
D
GERP RS
5.1
Varity_R
0.53
gMVP
0.67

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.

Other links and lift over

dbSNP: rs569826109; hg19: chr2-182468729; API