22-38294176-G-A

Variant names:

• chr22-38294176-G-A
• rs200745813
• NM_152221.3:c.1151C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_152221.3(CSNK1E):​c.1151C>T​(p.Ala384Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,054 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CSNK1E NM_152221.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.55

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4230448).
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSNK1E	NM_152221.3	c.1151C>T	p.Ala384Val	missense_variant	Exon 9 of 11	ENST00000396832.6	NP_689407.1
TPTEP2-CSNK1E	NM_001289912.2	c.1151C>T	p.Ala384Val	missense_variant	Exon 13 of 15		NP_001276841.1
CSNK1E	NM_001894.5	c.1151C>T	p.Ala384Val	missense_variant	Exon 9 of 11		NP_001885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSNK1E	ENST00000396832.6	c.1151C>T	p.Ala384Val	missense_variant	Exon 9 of 11	1	NM_152221.3	ENSP00000380044.1
TPTEP2-CSNK1E	ENST00000400206.7	c.1151C>T	p.Ala384Val	missense_variant	Exon 13 of 15	2		ENSP00000383067.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000324 AC: 8 AN: 246582 Hom.: 0 AF XY: 0.0000597 AC XY: 8 AN XY: 134084

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000718

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1459754 Hom.: 0 Cov.: 33 AF XY: 0.0000207 AC XY: 15 AN XY: 726212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74480

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000359 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000495 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1151C>T (p.A384V) alteration is located in exon 9 (coding exon 8) of the CSNK1E gene. This alteration results from a C to T substitution at nucleotide position 1151, causing the alanine (A) at amino acid position 384 to be replaced by a valine (V). 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	0.23
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;T;T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;.;.
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.55	N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.044	D;D;D;D
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.015	B;B;B;.
Vest4		0.77
MutPred		0.15		Gain of catalytic residue at A384 (P = 0.0787);Gain of catalytic residue at A384 (P = 0.0787);Gain of catalytic residue at A384 (P = 0.0787);Gain of catalytic residue at A384 (P = 0.0787);
MVP		0.67
MPC		0.72
ClinPred		0.53	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200745813; hg19: chr22-38690182;