16-23988588-G-T

Position:

• chr16-23988588-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002738.7(PRKCB):​c.286G>T​(p.Asp96Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PRKCB NM_002738.7 missense, splice_region
• Scores: Splicing: ADA: 0.9677
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.57

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCB	NM_002738.7	c.286G>T	p.Asp96Tyr	missense_variant, splice_region_variant	3/17	ENST00000643927.1	NP_002729.2
PRKCB	NM_212535.3	c.286G>T	p.Asp96Tyr	missense_variant, splice_region_variant	3/17		NP_997700.1
PRKCB	XM_047434365.1	c.-102G>T		splice_region_variant	2/16		XP_047290321.1
PRKCB	XM_047434365.1	c.-102G>T		5_prime_UTR_variant	2/16		XP_047290321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCB	ENST00000643927.1	c.286G>T	p.Asp96Tyr	missense_variant, splice_region_variant	3/17		NM_002738.7	ENSP00000496129.1
PRKCB	ENST00000321728.12	c.286G>T	p.Asp96Tyr	missense_variant, splice_region_variant	3/17	1		ENSP00000318315.7
PRKCB	ENST00000498739.1	c.-26-104203G>T		intron_variant		4		ENSP00000459227.1
PRKCB	ENST00000647422.1	n.186G>T		splice_region_variant, non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250826 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135514

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461436 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727050

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.00000378

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

Jun 16, 2024

The c.286G>T (p.D96Y) alteration is located in exon 3 (coding exon 3) of the PRKCB gene. This alteration results from a G to T substitution at nucleotide position 286, causing the aspartic acid (D) at amino acid position 96 to be replaced by a tyrosine (Y). 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	0.90
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.1	M;M;M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.5	.;D;.;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	.;D;.;D
Sift4G	Uncertain	0.0080	.;D;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.66, 0.80
MutPred		0.21		Gain of methylation at K91 (P = 0.0379);Gain of methylation at K91 (P = 0.0379);Gain of methylation at K91 (P = 0.0379);Gain of methylation at K91 (P = 0.0379);
MVP		0.96
MPC		1.8
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.020		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: rs751886977; hg19: chr16-23999909;