2-46086299-G-A

Position:

• chr2-46086299-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005400.3(PRKCE):​c.1529G>A​(p.Arg510Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00534 in 1,599,648 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (31 hom.)
• Consequence: PRKCE NM_005400.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.78

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01808688).
• BP6: Variant 2-46086299-G-A is Benign according to our data. Variant chr2-46086299-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2650870.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-46086299-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 667 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCE	NM_005400.3	c.1529G>A	p.Arg510Gln	missense_variant	11/15	ENST00000306156.8	NP_005391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCE	ENST00000306156.8	c.1529G>A	p.Arg510Gln	missense_variant	11/15	1	NM_005400.3	ENSP00000306124.3
PRKCE	ENST00000469753.5	n.616G>A		non_coding_transcript_exon_variant	2/4	3
PRKCE	ENST00000480633.1	n.295G>A		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 667 AN: 152130 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00756

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00641

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00455 AC: 1078 AN: 237006 Hom.: 2 AF XY: 0.00412 AC XY: 534 AN XY: 129548

Gnomad AFR exome AF: 0.000992

Gnomad AMR exome AF: 0.00578

Gnomad ASJ exome AF: 0.000602

Gnomad EAS exome AF: 0.000283

Gnomad SAS exome AF: 0.000622

Gnomad FIN exome AF: 0.00736

Gnomad NFE exome AF: 0.00641

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00544 AC: 7871 AN: 1447400 Hom.: 31 Cov.: 31 AF XY: 0.00523 AC XY: 3768 AN XY: 720422

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.00851

Gnomad4 NFE exome AF: 0.00620

Gnomad4 OTH exome AF: 0.00385

GnomAD4 genome AF: 0.00438 AC: 667 AN: 152248 Hom.: 2 Cov.: 32 AF XY: 0.00399 AC XY: 297 AN XY: 74412

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00756

Gnomad4 NFE AF: 0.00641

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00530 Hom.: 7

Bravo AF: 0.00408

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00108 AC: 4

ESP6500EA AF: 0.00607 AC: 46

ExAC AF: 0.00445 AC: 528

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00556

EpiControl AF: 0.00593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

PRKCE: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.32
Sift	Benign	0.23	T
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.84
MVP		0.87
MPC		1.5
ClinPred		0.033	T
GERP RS		4.7
Varity_R		0.44
gMVP		0.86

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: rs74990336; hg19: chr2-46313438;