chr16-24123911-G-C

Position:

chr16-24123911-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_002738.7(PRKCB):c.995G>C(p.Gly332Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

PRKCB
NM_002738.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 9.37

Variant links:

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]

PRKCB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16983408).

BP6

Variant 16-24123911-G-C is Benign according to our data. Variant chr16-24123911-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2570935.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCB	NM_002738.7 linkuse as main transcript	c.995G>C	p.Gly332Ala	missense_variant	9/17	ENST00000643927.1	NP_002729.2	P05771-2
PRKCB	NM_212535.3 linkuse as main transcript	c.995G>C	p.Gly332Ala	missense_variant	9/17		NP_997700.1	P05771-1
PRKCB	XM_047434365.1 linkuse as main transcript	c.608G>C	p.Gly203Ala	missense_variant	8/16		XP_047290321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCB	ENST00000643927.1 linkuse as main transcript	c.995G>C	p.Gly332Ala	missense_variant	9/17		NM_002738.7	ENSP00000496129.1		P05771-2
PRKCB	ENST00000321728.12 linkuse as main transcript	c.995G>C	p.Gly332Ala	missense_variant	9/17	1		ENSP00000318315.7		P05771-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000397

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000191

AC:

AN:

251424

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.000378

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000265

AC:

388

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

197

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000325

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000204

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000402

Hom.:

Bravo

AF:

0.000280

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

PRKCB-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2023

The PRKCB c.995G>C variant is predicted to result in the amino acid substitution p.Gly332Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.036% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-24135232-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

PRKCB: PP2, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Benign

0.88

DEOGEN2

Benign

0.30

T;T;.;.

Eigen

Benign

-0.053

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

.;D;.;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

2.0

M;M;M;M

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.38

.;N;.;N

REVEL

Benign

0.28

Sift

Benign

0.66

.;T;.;T

Sift4G

Benign

0.31

.;T;.;T

Polyphen

0.0

B;B;B;B

Vest4

0.70, 0.74

MVP

0.89

MPC

1.2

ClinPred

0.15

GERP RS

4.9

Varity_R

0.12

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over