19-53882648-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong

The NM_002739.5(PRKCG):​c.154T>C​(p.Cys52Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C52S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

PRKCG
NM_002739.5 missense

Scores

14
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.36
Variant links:
Genes affected
PRKCG (HGNC:9402): (protein kinase C gamma) 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 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 distinct roles in cells. The protein encoded by this gene is one of the PKC family members. This protein kinase is expressed solely in the brain and spinal cord and its localization is restricted to neurons. It has been demonstrated that several neuronal functions, including long term potentiation (LTP) and long term depression (LTD), specifically require this kinase. Knockout studies in mice also suggest that this kinase may be involved in neuropathic pain development. Defects in this protein have been associated with neurodegenerative disorder spinocerebellar ataxia-14 (SCA14). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a zinc_finger_region Phorbol-ester/DAG-type 1 (size 50) in uniprot entity KPCG_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002739.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-53882648-T-A is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in the PRKCG gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 3.0601 (below the threshold of 3.09). Trascript score misZ: 3.8304 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 14.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRKCGNM_002739.5 linkc.154T>C p.Cys52Arg missense_variant Exon 1 of 18 ENST00000263431.4 NP_002730.1 P05129-1
PRKCGNM_001316329.2 linkc.154T>C p.Cys52Arg missense_variant Exon 1 of 19 NP_001303258.1 P05129B7Z3W6B2R5T1A0A804HIU5
PRKCGXM_047439092.1 linkc.-231T>C 5_prime_UTR_variant Exon 2 of 20 XP_047295048.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRKCGENST00000263431.4 linkc.154T>C p.Cys52Arg missense_variant Exon 1 of 18 1 NM_002739.5 ENSP00000263431.3 P05129-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
62
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Apr 26, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
D
Eigen
Pathogenic
0.81
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Pathogenic
4.8
H
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-9.2
D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.82
MutPred
0.98
Gain of MoRF binding (P = 0.069);
MVP
0.98
MPC
3.9
ClinPred
1.0
D
GERP RS
3.8
Varity_R
0.99
gMVP
1.0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-54385902; API