16-23988577-G-A

Variant names:

• chr16-23988577-G-A
• rs1131692056
• NM_002738.7:c.275G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_002738.7(PRKCB):​c.275G>A​(p.Gly92Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G92V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRKCB NM_002738.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.57
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-23988577-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 224499.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCB	NM_002738.7	c.275G>A	p.Gly92Asp	missense_variant	Exon 3 of 17	ENST00000643927.1	NP_002729.2
PRKCB	NM_212535.3	c.275G>A	p.Gly92Asp	missense_variant	Exon 3 of 17		NP_997700.1
PRKCB	XM_047434365.1	c.-113G>A		5_prime_UTR_variant	Exon 2 of 16		XP_047290321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCB	ENST00000643927.1	c.275G>A	p.Gly92Asp	missense_variant	Exon 3 of 17		NM_002738.7	ENSP00000496129.1
PRKCB	ENST00000321728.12	c.275G>A	p.Gly92Asp	missense_variant	Exon 3 of 17	1		ENSP00000318315.7
PRKCB	ENST00000647422.1	n.175G>A		non_coding_transcript_exon_variant	Exon 2 of 5
PRKCB	ENST00000498739.1	c.-26-104214G>A		intron_variant	Intron 1 of 3	4		ENSP00000459227.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461760 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727198

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111908

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	.;D;.;D
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.9	M;M;M;M
PhyloP100		9.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.0	.;D;.;D
REVEL	Uncertain	0.45
Sift	Benign	0.17	.;T;.;T
Sift4G	Benign	0.30	.;T;.;T
Polyphen		0.90	P;P;P;P
Vest4		0.70, 0.85
MutPred		0.23		Loss of catalytic residue at G92 (P = 0.0233);Loss of catalytic residue at G92 (P = 0.0233);Loss of catalytic residue at G92 (P = 0.0233);Loss of catalytic residue at G92 (P = 0.0233);
MVP		0.88
MPC		2.0
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.84
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs1131692056; hg19: chr16-23999898;