2-46007549-G-C

Position:

• chr2-46007549-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005400.3(PRKCE):​c.1151G>C​(p.Gly384Ala) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRKCE NM_005400.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

Genes affected

PRKCE (HGNC:9401): (protein kinase C epsilon) Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. This kinase has been shown to be involved in many different cellular functions, such as neuron channel activation, apoptosis, cardioprotection from ischemia, heat shock response, as well as insulin exocytosis. Knockout studies in mice suggest that this kinase is important for lipopolysaccharide (LPS)-mediated signaling in activated macrophages and may also play a role in controlling anxiety-like behavior. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PRKCE
• BP4: Computational evidence support a benign effect (MetaRNN=0.11398694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKCE	NM_005400.3	c.1151G>C	p.Gly384Ala	missense_variant	9/15	ENST00000306156.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCE	ENST00000306156.8	c.1151G>C	p.Gly384Ala	missense_variant	9/15	1	NM_005400.3	P1
PRKCE	ENST00000394874.1	c.320G>C	p.Gly107Ala	missense_variant	4/6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000422 AC: 1 AN: 236956 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129514

Gnomad AFR exome AF: 0.0000662

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.1151G>C (p.G384A) alteration is located in exon 9 (coding exon 9) of the PRKCE gene. This alteration results from a G to C substitution at nucleotide position 1151, causing the glycine (G) at amino acid position 384 to be replaced by an alanine (A). 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	0.069
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.078
Sift	Benign	0.13	T;T
Sift4G	Benign	0.26	T;D
Polyphen		0.0	B;.
Vest4		0.089
MutPred		0.28		Gain of relative solvent accessibility (P = 0.09);.;
MVP		0.62
MPC		0.67
ClinPred		0.14	T
GERP RS		5.5
Varity_R		0.037
gMVP		0.35

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: rs919285181; hg19: chr2-46234688;