22-38294458-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_152221.3(CSNK1E):​c.962G>A​(p.Arg321Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,582,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: CSNK1E NM_152221.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.82

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0371103).
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSNK1E	NM_152221.3	c.962G>A	p.Arg321Gln	missense_variant	Exon 8 of 11	ENST00000396832.6	NP_689407.1
TPTEP2-CSNK1E	NM_001289912.2	c.962G>A	p.Arg321Gln	missense_variant	Exon 12 of 15		NP_001276841.1
CSNK1E	NM_001894.5	c.962G>A	p.Arg321Gln	missense_variant	Exon 8 of 11		NP_001885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSNK1E	ENST00000396832.6	c.962G>A	p.Arg321Gln	missense_variant	Exon 8 of 11	1	NM_152221.3	ENSP00000380044.1
TPTEP2-CSNK1E	ENST00000400206.7	c.962G>A	p.Arg321Gln	missense_variant	Exon 12 of 15	2		ENSP00000383067.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000994 AC: 19 AN: 191172 Hom.: 0 AF XY: 0.0000762 AC XY: 8 AN XY: 104988

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00112

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000376

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000224 AC: 32 AN: 1430378 Hom.: 0 Cov.: 35 AF XY: 0.0000183 AC XY: 13 AN XY: 709418

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000241

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000375

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000911

Gnomad4 OTH exome AF: 0.000102

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000451 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000751 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.962G>A (p.R321Q) alteration is located in exon 8 (coding exon 7) of the CSNK1E gene. This alteration results from a G to A substitution at nucleotide position 962, causing the arginine (R) at amino acid position 321 to be replaced by a glutamine (Q). 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	0.16
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	.;D;.;.
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.037	T;T;T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.16	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.91	P;P;P;.
Vest4		0.41
MutPred		0.27		Loss of MoRF binding (P = 0.0352);Loss of MoRF binding (P = 0.0352);Loss of MoRF binding (P = 0.0352);Loss of MoRF binding (P = 0.0352);
MVP		0.62
MPC		1.4
ClinPred		0.15	T
GERP RS		5.6
Varity_R		0.085
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs777001542; hg19: chr22-38690464;