1-2173988-C-G

Variant names:

• chr1-2173988-C-G
• rs142352833
• NM_002744.6:c.1377C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002744.6(PRKCZ):​c.1377C>G​(p.Asp459Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D459D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKCZ NM_002744.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• Publications: 3 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2755581).

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.1377C>G	p.Asp459Glu	missense	Exon 14 of 18	NP_002735.3
	PRKCZ	NM_001242874.3		c.1065C>G	p.Asp355Glu	missense	Exon 11 of 15	NP_001229803.1	Q05513-3
	PRKCZ	NM_001350803.2		c.852C>G	p.Asp284Glu	missense	Exon 11 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.1377C>G	p.Asp459Glu	missense	Exon 14 of 18	ENSP00000367830.3	Q05513-1
	PRKCZ	ENST00000400921.6	TSL:1	c.828C>G	p.Asp276Glu	missense	Exon 11 of 15	ENSP00000383712.2	Q05513-2
	PRKCZ	ENST00000965048.1		c.1650C>G	p.Asp550Glu	missense	Exon 15 of 19	ENSP00000635107.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.73
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.89	L
PhyloP100		1.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.26
Sift	Benign	0.38	T
Sift4G	Benign	0.12	T
Polyphen		0.035	B
Vest4		0.63
MutPred		0.51		Gain of disorder (P = 0.1422)
MVP		0.61
MPC		1.2
ClinPred		0.45	T
GERP RS		3.0
Varity_R		0.35
Mutation Taster		=76/24	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs142352833; hg19: chr1-2105427;