2-181604002-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM5PP5_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 Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CERKL
NM_201548.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.85

Publications

11 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: Pathogenic. The variant received 10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-181604002-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1308275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 2-181604002-G-T is Pathogenic according to our data. Variant chr2-181604002-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 438054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CERKL	NM_201548.5	MANE Select	c.316C>A	p.Arg106Ser	missense	Exon 2 of 13	NP_963842.1	Q49MI3-2
CERKL	NM_001030311.3		c.316C>A	p.Arg106Ser	missense	Exon 2 of 14	NP_001025482.1	Q49MI3-1
CERKL	NM_001160277.2		c.316C>A	p.Arg106Ser	missense	Exon 2 of 13	NP_001153749.1	Q49MI3-9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CERKL	ENST00000410087.8	TSL:1 MANE Select	c.316C>A	p.Arg106Ser	missense	Exon 2 of 13	ENSP00000386725.3	Q49MI3-2
CERKL	ENST00000339098.9	TSL:1	c.316C>A	p.Arg106Ser	missense	Exon 2 of 14	ENSP00000341159.5	Q49MI3-1
CERKL	ENST00000374970.6	TSL:1	c.316C>A	p.Arg106Ser	missense	Exon 2 of 11	ENSP00000364109.2	Q49MI3-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151950

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000520

AC:

AN:

249812

AF XY:

0.0000740

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000377

AC:

AN:

1460422

Hom.:

Cov.:

AF XY:

0.0000647

AC XY:

AN XY:

726524

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39530

South Asian (SAS)

AF:

0.000615

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111104

Other (OTH)

AF:

0.0000331

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41494

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000626

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67976

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ExAC

AF:

0.0000659

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Retinitis pigmentosa 26 (6)

not provided (2)

Retinal dystrophy (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.054

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.5

PhyloP100

7.8

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.37

Sift

Benign

0.099

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.81

MutPred

0.63

Loss of MoRF binding (P = 0.0266)

MVP

0.73

MPC

0.52

ClinPred

0.86

GERP RS

5.1

Varity_R

0.53

gMVP

0.67

Mutation Taster

=0/100

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over