rs863224855

Variant names:

• chr2-181566061-T-A
• rs863224855
• NM_201548.5:c.674A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_201548.5(CERKL):​c.674A>T​(p.Asp225Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D225D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CERKL NM_201548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.17
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 2-181566061-T-A is Pathogenic according to our data. Variant chr2-181566061-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242528.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERKL	NM_201548.5	MANE Select	c.674A>T	p.Asp225Val	missense	Exon 4 of 13	NP_963842.1
	CERKL	NM_001030311.3		c.674A>T	p.Asp225Val	missense	Exon 4 of 14	NP_001025482.1
	CERKL	NM_001160277.2		c.542A>T	p.Asp181Val	missense	Exon 3 of 13	NP_001153749.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERKL	ENST00000410087.8	TSL:1 MANE Select	c.674A>T	p.Asp225Val	missense	Exon 4 of 13	ENSP00000386725.3
	CERKL	ENST00000339098.9	TSL:1	c.674A>T	p.Asp225Val	missense	Exon 4 of 14	ENSP00000341159.5
	CERKL	ENST00000374970.6	TSL:1	c.613+7692A>T		intron	N/A	ENSP00000364109.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.81		Loss of disorder (P = 0.0325)
MVP		0.77
MPC		0.58
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.75
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs863224855; hg19: chr2-182430788;