chr19-53882648-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. C52F) has been classified as Uncertain significance.

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]

Genome browser will be placed here

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 13 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 ClinVar as [Likely_pathogenic]. Clinvar id is 211956.Status of the report is criteria_provided_single_submitter, 1 stars.
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, 0.994

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRKCGNM_002739.5 linkuse as main transcriptc.154T>C p.Cys52Arg missense_variant 1/18 ENST00000263431.4
PRKCGNM_001316329.2 linkuse as main transcriptc.154T>C p.Cys52Arg missense_variant 1/19
PRKCGXM_047439092.1 linkuse as main transcriptc.-231T>C 5_prime_UTR_variant 2/20

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PRKCGENST00000263431.4 linkuse as main transcriptc.154T>C p.Cys52Arg missense_variant 1/181 NM_002739.5 P1P05129-1

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
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 26, 2022Not 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
MutationTaster
Benign
1.0
D;D;D
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