2-181604076-T-C

Variant names:

• chr2-181604076-T-C
• rs61750041
• NM_201548.5:c.242A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201548.5(CERKL):​c.242A>G​(p.Asp81Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D81A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CERKL NM_201548.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10922265).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERKL	NM_201548.5	MANE Select	c.242A>G	p.Asp81Gly	missense	Exon 2 of 13	NP_963842.1	Q49MI3-2
	CERKL	NM_001030311.3		c.242A>G	p.Asp81Gly	missense	Exon 2 of 14	NP_001025482.1	Q49MI3-1
	CERKL	NM_001160277.2		c.242A>G	p.Asp81Gly	missense	Exon 2 of 13	NP_001153749.1	Q49MI3-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERKL	ENST00000410087.8	TSL:1 MANE Select	c.242A>G	p.Asp81Gly	missense	Exon 2 of 13	ENSP00000386725.3	Q49MI3-2
	CERKL	ENST00000339098.9	TSL:1	c.242A>G	p.Asp81Gly	missense	Exon 2 of 14	ENSP00000341159.5	Q49MI3-1
	CERKL	ENST00000374970.6	TSL:1	c.242A>G	p.Asp81Gly	missense	Exon 2 of 11	ENSP00000364109.2	Q49MI3-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441658 Hom.: 0 Cov.: 29 AF XY: 0.00000278 AC XY: 2 AN XY: 718288

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32346

American (AMR) AF: 0.00 AC: 0 AN: 44396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39348

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095720

Other (OTH) AF: 0.00 AC: 0 AN: 59666

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.074
Sift	Benign	0.28	T
Sift4G	Benign	0.15	T
Polyphen		0.021	B
Vest4		0.28
MutPred		0.66		Gain of helix (P = 0.0325)
MVP		0.42
MPC		0.13
ClinPred		0.094	T
GERP RS		3.0
Varity_R		0.075
gMVP		0.41
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs61750041; hg19: chr2-182468803;