chr1-2175249-G-C

Variant names:

• chr1-2175249-G-C
• rs145374413
• NM_002744.6:c.1511G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002744.6(PRKCZ):​c.1511G>C​(p.Arg504Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,946 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. R504Q) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PRKCZ NM_002744.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.85
• Publications: 0 publications found

Genes affected

PRKCZ (HGNC:9412): (protein kinase C zeta) Protein kinase C (PKC) zeta is a member of the PKC family of serine/threonine kinases which are involved in a variety of cellular processes such as proliferation, differentiation and secretion. Unlike the classical PKC isoenzymes which are calcium-dependent, PKC zeta exhibits a kinase activity which is independent of calcium and diacylglycerol but not of phosphatidylserine. Furthermore, it is insensitive to typical PKC inhibitors and cannot be activated by phorbol ester. Unlike the classical PKC isoenzymes, it has only a single zinc finger module. These structural and biochemical properties indicate that the zeta subspecies is related to, but distinct from other isoenzymes of PKC. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002744.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCZ	NM_002744.6	MANE Select	c.1511G>C	p.Arg504Pro	missense	Exon 16 of 18	NP_002735.3
	PRKCZ	NM_001242874.3		c.1199G>C	p.Arg400Pro	missense	Exon 13 of 15	NP_001229803.1	Q05513-3
	PRKCZ	NM_001350803.2		c.986G>C	p.Arg329Pro	missense	Exon 13 of 15	NP_001337732.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCZ	ENST00000378567.8	TSL:1 MANE Select	c.1511G>C	p.Arg504Pro	missense	Exon 16 of 18	ENSP00000367830.3	Q05513-1
	PRKCZ	ENST00000400921.6	TSL:1	c.962G>C	p.Arg321Pro	missense	Exon 13 of 15	ENSP00000383712.2	Q05513-2
	PRKCZ	ENST00000965048.1		c.1784G>C	p.Arg595Pro	missense	Exon 17 of 19	ENSP00000635107.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151946 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151946 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74222

African (AFR) AF: 0.00 AC: 0 AN: 41326

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.3	L
PhyloP100		5.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.20
Sift	Benign	0.28	T
Sift4G	Benign	0.27	T
Polyphen		0.51	P
Vest4		0.59
MutPred		0.60		Loss of solvent accessibility (P = 0.1077)
MVP		0.81
MPC		0.35
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.61
Mutation Taster		=58/42	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145374413; hg19: chr1-2106688;