22-38294458-C-A

Variant names:

• chr22-38294458-C-A
• rs777001542
• NM_152221.3:c.962G>T

Variant summary

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

The NM_152221.3(CSNK1E):​c.962G>T​(p.Arg321Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,378 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R321W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CSNK1E NM_152221.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.82
• Publications: 0 publications found

Genes affected

CSNK1E (HGNC:2453): (casein kinase 1 epsilon) The protein encoded by this gene is a serine/threonine protein kinase and a member of the casein kinase I protein family, whose members have been implicated in the control of cytoplasmic and nuclear processes, including DNA replication and repair. The encoded protein is found in the cytoplasm as a monomer and can phosphorylate a variety of proteins, including itself. This protein has been shown to phosphorylate period, a circadian rhythm protein. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Feb 2014]

TPTEP2-CSNK1E (HGNC:53829): (TPTEP2-CSNK1E readthrough) This locus represents naturally occurring readthrough transcription between the neighboring LOC400927 (transmembrane phosphoinositide 3-phosphatase and tensin homolog 2 pseudogene) and CSNK1E (casein kinase I isoform epsilon) genes on chromosome 22. The readthrough transcript encodes the same protein as the downstream gene product (casein kinase I isoform epsilon). [provided by RefSeq, Feb 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152221.3. 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
	CSNK1E	NM_152221.3	MANE Select	c.962G>T	p.Arg321Leu	missense	Exon 8 of 11	NP_689407.1	P49674
	TPTEP2-CSNK1E	NM_001289912.2		c.962G>T	p.Arg321Leu	missense	Exon 12 of 15	NP_001276841.1
	CSNK1E	NM_001894.5		c.962G>T	p.Arg321Leu	missense	Exon 8 of 11	NP_001885.1	P49674

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSNK1E	ENST00000396832.6	TSL:1 MANE Select	c.962G>T	p.Arg321Leu	missense	Exon 8 of 11	ENSP00000380044.1	P49674
	CSNK1E	ENST00000359867.7	TSL:1	c.962G>T	p.Arg321Leu	missense	Exon 8 of 11	ENSP00000352929.3	P49674
	TPTEP2-CSNK1E	ENST00000400206.7	TSL:2	c.962G>T	p.Arg321Leu	missense	Exon 12 of 15	ENSP00000383067.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430378 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 709418

⚠️ 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: 32382

American (AMR) AF: 0.00 AC: 0 AN: 41422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25578

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37340

South Asian (SAS) AF: 0.00 AC: 0 AN: 82410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098254

Other (OTH) AF: 0.00 AC: 0 AN: 59082

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), 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	Uncertain	0.36
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.045
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.90	T
PhyloP100		2.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.20
Sift	Benign	0.085	T
Sift4G	Benign	0.20	T
Polyphen		0.38	B
Vest4		0.71
MutPred		0.34		Loss of MoRF binding (P = 0.0344)
MVP		0.77
MPC		1.5
ClinPred		0.94	D
GERP RS		5.6
PromoterAI		0.033	Neutral
Varity_R		0.14
gMVP		0.60
Mutation Taster		=77/23	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: rs777001542; hg19: chr22-38690464;