rs386134159
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_002739.5(PRKCG):c.188G>T(p.Gly63Val) variant causes a missense change. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G63R) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 31)
Consequence
PRKCG
NM_002739.5 missense
NM_002739.5 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 6.36
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 13 ACMG points.
PM1
In a zinc_finger_region Phorbol-ester/DAG-type 1 (size 50) in uniprot entity KPCG_HUMAN there are 12 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 chrnull-null-null-null is described in UniProt as null.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PRKCG. . Gene score misZ 3.0601 (greater than the threshold 3.09). Trascript score misZ 3.8304 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 14.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 19-53883180-G-T is Pathogenic according to our data. Variant chr19-53883180-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42140.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRKCG | NM_002739.5 | c.188G>T | p.Gly63Val | missense_variant | 2/18 | ENST00000263431.4 | |
PRKCG | NM_001316329.2 | c.188G>T | p.Gly63Val | missense_variant | 2/19 | ||
PRKCG | XM_047439092.1 | c.-197G>T | 5_prime_UTR_variant | 3/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRKCG | ENST00000263431.4 | c.188G>T | p.Gly63Val | missense_variant | 2/18 | 1 | NM_002739.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 09, 2019 | DNA sequence analysis of the PRKCG gene demonstrated a sequence change, c.188G>T, in exon 2 that results in an amino acid change, p.Gly63Val. The p.Gly63Val change affects a highly conserved amino acid residue located in the C1A subdomain of the PRKCG protein that is known to be functional. This particular amino acid change was identified in an individual with slowly progressive gait ataxia, mildly disturbed balance, nystagmus, dysarthria, non-progressive cerebellar atrophy and three-generation family history of mild gait ataxia. Father of this individual who presented with mild gait ataxia and disturbed balance, also had this variant; however other family members were not tested. A different pathogenic sequence change affecting the same amino acid residue (p.Gly63Arg) has been described in multiple individuals from a family with suspected autosomal dominant cerebellar ataxia (Nibbeling et al., 2017). Transiently transfected HEK293T cells showed that both the p.Gly63Arg and Gly63Val sequence changes lead to loss of phorbol-ester induced C1A subdomain plasma-membrane translocation indicating an impact on activation of PKC gamma domain (Nibbeling et al., 2017). This sequence change has not been described in the population databases (ExAC and gnomAD). The p.Gly63Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). - |
Spinocerebellar ataxia type 14 Pathogenic:1
Pathogenic, no assertion criteria provided | curation | GeneReviews | Apr 18, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of relative solvent accessibility (P = 0.0479);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at