16-24113044-A-G

Position:

• chr16-24113044-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002738.7(PRKCB):​c.893A>G​(p.Asn298Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000938 in 1,612,696 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00094 (1 hom.)
• Consequence: PRKCB NM_002738.7 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.08

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031681746).
• BP6: Variant 16-24113044-A-G is Benign according to our data. Variant chr16-24113044-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3049670.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCB	NM_002738.7	c.893A>G	p.Asn298Ser	missense_variant	8/17	ENST00000643927.1	NP_002729.2
PRKCB	NM_212535.3	c.893A>G	p.Asn298Ser	missense_variant	8/17		NP_997700.1
PRKCB	XM_047434365.1	c.506A>G	p.Asn169Ser	missense_variant	7/16		XP_047290321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCB	ENST00000643927.1	c.893A>G	p.Asn298Ser	missense_variant	8/17		NM_002738.7	ENSP00000496129.1
PRKCB	ENST00000321728.12	c.893A>G	p.Asn298Ser	missense_variant	8/17	1		ENSP00000318315.7
PRKCB	ENST00000498739.1	c.338A>G	p.Asn113Ser	missense_variant	4/4	4		ENSP00000459227.1

Frequencies

GnomAD3 genomes AF: 0.000880 AC: 134 AN: 152224 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

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: 0.00129

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000828 AC: 207 AN: 249928 Hom.: 0 AF XY: 0.000829 AC XY: 112 AN XY: 135068

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.000934

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000944 AC: 1379 AN: 1460354 Hom.: 1 Cov.: 30 AF XY: 0.000936 AC XY: 680 AN XY: 726486

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000830

Gnomad4 ASJ exome AF: 0.000422

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.000746

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152342 Hom.: 0 Cov.: 31 AF XY: 0.000872 AC XY: 65 AN XY: 74500

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000978 Hom.: 0

Bravo AF: 0.000982

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000881 AC: 107

EpiCase AF: 0.00125

EpiControl AF: 0.00161

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PRKCB-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;D;.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.032	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.3	M;M;M;M;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.65	.;N;.;N;.
REVEL	Benign	0.14
Sift	Benign	0.38	.;T;.;T;.
Sift4G	Benign	0.86	.;T;.;T;T
Polyphen		0.0080	B;B;B;B;.
Vest4		0.19, 0.24
MVP		0.81
MPC		0.89
ClinPred		0.040	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.064
gMVP		0.43

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: rs147975795; hg19: chr16-24124365;