16-24154768-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_002738.7(PRKCB):c.1150G>A(p.Val384Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: PRKCB NM_002738.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

PRKCB (HGNC:9395): (protein kinase C beta) Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and 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 protein kinase has been reported to be involved in many different cellular functions, such as B cell activation, apoptosis induction, endothelial cell proliferation, and intestinal sugar absorption. Studies in mice also suggest that this kinase may also regulate neuronal functions and correlate fear-induced conflict behavior after stress. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PRKCB
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKCB	NM_002738.7	c.1150G>A	p.Val384Met	missense_variant	10/17	ENST00000643927.1
PRKCB	NM_212535.3	c.1150G>A	p.Val384Met	missense_variant	10/17
PRKCB	XM_047434365.1	c.763G>A	p.Val255Met	missense_variant	9/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCB	ENST00000643927.1	c.1150G>A	p.Val384Met	missense_variant	10/17		NM_002738.7	A1
PRKCB	ENST00000321728.12	c.1150G>A	p.Val384Met	missense_variant	10/17	1		P4
PRKCB	ENST00000472066.1	c.91G>A	p.Val31Met	missense_variant	2/5	3

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251370 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135852

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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461876 Hom.: 0 Cov.: 30 AF XY: 0.0000481 AC XY: 35 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74376

Gnomad4 AFR AF: 0.0000483

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: 0.000103

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2022

The c.1150G>A (p.V384M) alteration is located in exon 10 (coding exon 10) of the PRKCB gene. This alteration results from a G to A substitution at nucleotide position 1150, causing the valine (V) at amino acid position 384 to be replaced by a methionine (M). 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	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.3	L;L;L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
Polyphen		0.99	D;D;D;D;.
Vest4		0.79, 0.73
MVP		0.79
MPC		2.1
ClinPred		0.75	D
GERP RS		5.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.55
gMVP		0.70

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: rs200238437; hg19: chr16-24166089;