Genetic Variant NM_002738.7:c.286G>A (chr16-23988588-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4BS2

The NM_002738.7(PRKCB):c.286G>A(p.Asp96Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PRKCB
NM_002738.7 missense, splice_region

Scores

Splicing: ADA: 0.9370

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.57

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37918288).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCB	NM_002738.7 link	c.286G>A	p.Asp96Asn	missense_variant, splice_region_variant	Exon 3 of 17	ENST00000643927.1	NP_002729.2	P05771-2
PRKCB	NM_212535.3 link	c.286G>A	p.Asp96Asn	missense_variant, splice_region_variant	Exon 3 of 17		NP_997700.1	P05771-1
PRKCB	XM_047434365.1 link	c.-102G>A		splice_region_variant	Exon 2 of 16		XP_047290321.1
PRKCB	XM_047434365.1 link	c.-102G>A		5_prime_UTR_variant	Exon 2 of 16		XP_047290321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRKCB	ENST00000643927.1 link	c.286G>A	p.Asp96Asn	missense_variant, splice_region_variant	Exon 3 of 17		NM_002738.7	ENSP00000496129.1	P05771-2
PRKCB	ENST00000321728.12 link	c.286G>A	p.Asp96Asn	missense_variant, splice_region_variant	Exon 3 of 17	1		ENSP00000318315.7	P05771-1
PRKCB	ENST00000498739.1 link	c.-26-104203G>A		intron_variant	Intron 1 of 3	4		ENSP00000459227.1	I3L1Z0
PRKCB	ENST00000647422.1 link	n.186G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250826

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135514

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461436

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

D;D;.;.

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;D;.;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.38

T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Uncertain

2.1

M;M;M;M

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.8

.;D;.;D

REVEL

Benign

0.26

Sift

Uncertain

0.026

.;D;.;D

Sift4G

Benign

0.079

.;T;.;T

Polyphen

0.86

P;P;P;P

Vest4

0.71, 0.71

MutPred

0.20

Loss of phosphorylation at S95 (P = 0.1114);Loss of phosphorylation at S95 (P = 0.1114);Loss of phosphorylation at S95 (P = 0.1114);Loss of phosphorylation at S95 (P = 0.1114);

MVP

0.87

MPC

1.5

ClinPred

0.85

GERP RS

5.6

Varity_R

0.33

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.94

dbscSNV1_RF

Pathogenic

0.73

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over