22-46695334-G-A

Variant names:

• chr22-46695334-G-A
• rs9616098
• NM_022766.6:c.944-19C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_022766.6(CERK):​c.944-19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,413,760 control chromosomes in the GnomAD database, including 285 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.013 (16 hom., cov: 33)
  • Exomes 𝑓: 0.018 (269 hom.)
• Consequence: CERK NM_022766.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.685
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0129 (1962/152330) while in subpopulation SAS AF = 0.0288 (139/4830). AF 95% confidence interval is 0.0249. There are 16 homozygotes in GnomAd4. There are 984 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022766.6. 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
	CERK	NM_022766.6	MANE Select	c.944-19C>T		intron	N/A	NP_073603.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERK	ENST00000216264.13	TSL:1 MANE Select	c.944-19C>T		intron	N/A	ENSP00000216264.8
	CERK	ENST00000443629.5	TSL:1	n.*322-19C>T		intron	N/A	ENSP00000400859.1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1964 AN: 152212 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.0153 AC: 3841 AN: 250962 AF XY: 0.0168

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00538

Gnomad ASJ exome AF: 0.00943

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.0188

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0177 AC: 22359 AN: 1261430 Hom.: 269 Cov.: 19 AF XY: 0.0184 AC XY: 11762 AN XY: 637968

African (AFR) AF: 0.00303 AC: 89 AN: 29416

American (AMR) AF: 0.00544 AC: 242 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.00916 AC: 228 AN: 24888

East Asian (EAS) AF: 0.000516 AC: 20 AN: 38786

South Asian (SAS) AF: 0.0299 AC: 2458 AN: 82246

European-Finnish (FIN) AF: 0.0211 AC: 1118 AN: 53070

Middle Eastern (MID) AF: 0.0121 AC: 65 AN: 5380

European-Non Finnish (NFE) AF: 0.0186 AC: 17321 AN: 929366

Other (OTH) AF: 0.0152 AC: 818 AN: 53824

GnomAD4 genome AF: 0.0129 AC: 1962 AN: 152330 Hom.: 16 Cov.: 33 AF XY: 0.0132 AC XY: 984 AN XY: 74500

African (AFR) AF: 0.00373 AC: 155 AN: 41592

American (AMR) AF: 0.00686 AC: 105 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0288 AC: 139 AN: 4830

European-Finnish (FIN) AF: 0.0213 AC: 226 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0188 AC: 1276 AN: 68018

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.0158 Hom.: 39

Bravo AF: 0.0111

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.17
DANN	Benign	0.33
PhyloP100		-0.69
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs9616098; hg19: chr22-47091231; COSMIC: COSV107239438; COSMIC: COSV107239438;