chr16-24123923-G-A

Position:

• chr16-24123923-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002738.7(PRKCB):​c.1007G>A​(p.Arg336Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PRKCB NM_002738.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.37

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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCB	NM_002738.7	c.1007G>A	p.Arg336Gln	missense_variant	9/17	ENST00000643927.1	NP_002729.2
PRKCB	NM_212535.3	c.1007G>A	p.Arg336Gln	missense_variant	9/17		NP_997700.1
PRKCB	XM_047434365.1	c.620G>A	p.Arg207Gln	missense_variant	8/16		XP_047290321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCB	ENST00000643927.1	c.1007G>A	p.Arg336Gln	missense_variant	9/17		NM_002738.7	ENSP00000496129.1
PRKCB	ENST00000321728.12	c.1007G>A	p.Arg336Gln	missense_variant	9/17	1		ENSP00000318315.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727236

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

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

Dec 21, 2022

The c.1007G>A (p.R336Q) alteration is located in exon 9 (coding exon 9) of the PRKCB gene. This alteration results from a G to A substitution at nucleotide position 1007, causing the arginine (R) at amino acid position 336 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	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	.;D;.;D
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.4	M;M;M;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.1	.;N;.;N
REVEL	Uncertain	0.31
Sift	Benign	0.14	.;T;.;T
Sift4G	Benign	0.43	.;T;.;T
Polyphen		0.012	B;B;B;B
Vest4		0.77, 0.83
MutPred		0.38		Loss of MoRF binding (P = 0.046);Loss of MoRF binding (P = 0.046);Loss of MoRF binding (P = 0.046);Loss of MoRF binding (P = 0.046);
MVP		0.88
MPC		1.2
ClinPred		0.94	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.24
gMVP		0.73

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: rs1163412779; hg19: chr16-24135244; COSMIC: COSV57768797;