NM_002744.6:c.146G>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002744.6(PRKCZ):​c.146G>T​(p.Arg49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 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. R49H) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PRKCZ
NM_002744.6 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.12
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11711675).
BS2
High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRKCZNM_002744.6 linkc.146G>T p.Arg49Leu missense_variant Exon 2 of 18 ENST00000378567.8 NP_002735.3 Q05513-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRKCZENST00000378567.8 linkc.146G>T p.Arg49Leu missense_variant Exon 2 of 18 1 NM_002744.6 ENSP00000367830.3 Q05513-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1461780
Hom.:
0
Cov.:
30
AF XY:
0.0000151
AC XY:
11
AN XY:
727190
show subpopulations
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:
0.0000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
16
DANN
Benign
0.94
DEOGEN2
Uncertain
0.42
T;.;T
Eigen
Benign
-0.83
Eigen_PC
Benign
-0.83
FATHMM_MKL
Benign
0.20
N
LIST_S2
Benign
0.31
T;T;T
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.12
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L;.;.
PrimateAI
Benign
0.32
T
PROVEAN
Uncertain
-2.9
D;D;D
REVEL
Benign
0.10
Sift
Benign
0.73
T;T;T
Sift4G
Benign
0.19
T;T;T
Polyphen
0.012
B;.;.
Vest4
0.35
MutPred
0.46
Loss of helix (P = 0.0123);Loss of helix (P = 0.0123);.;
MVP
0.55
MPC
0.35
ClinPred
0.33
T
GERP RS
2.9
Varity_R
0.28

Splicing

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.

Other links and lift over

dbSNP: rs35271800; hg19: chr1-1986954; API