22-46690140-T-G

Variant names:

• chr22-46690140-T-G
• NM_022766.6:c.1393A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022766.6(CERK):​c.1393A>C​(p.Met465Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CERK NM_022766.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.553

Genes affected

CERK (HGNC:19256): (ceramide kinase) CERK converts ceramide to ceramide 1-phosphate (C1P), a sphingolipid metabolite. Both CERK and C1P have been implicated in various cellular processes, including proliferation, apoptosis, phagocytosis, and inflammation (Kim et al., 2006 [PubMed 16488390]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038577765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERK	NM_022766.6	c.1393A>C	p.Met465Leu	missense_variant	Exon 12 of 13	ENST00000216264.13	NP_073603.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERK	ENST00000216264.13	c.1393A>C	p.Met465Leu	missense_variant	Exon 12 of 13	1	NM_022766.6	ENSP00000216264.8
CERK	ENST00000443629.5	n.*771A>C		non_coding_transcript_exon_variant	Exon 11 of 12	1		ENSP00000400859.1
CERK	ENST00000443629.5	n.*771A>C		3_prime_UTR_variant	Exon 11 of 12	1		ENSP00000400859.1
CERK	ENST00000471929.1	n.482A>C		non_coding_transcript_exon_variant	Exon 4 of 4	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1393A>C (p.M465L) alteration is located in exon 12 (coding exon 12) of the CERK gene. This alteration results from a A to C substitution at nucleotide position 1393, causing the methionine (M) at amino acid position 465 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.0020
DANN	Benign	0.35
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.020
Sift	Benign	0.83	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.28		Gain of relative solvent accessibility (P = 0.0166);
MVP		0.14
MPC		0.18
ClinPred		0.022	T
GERP RS		-7.9
Varity_R		0.025
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-47086037;