rs386134159

Variant names:

• chr19-53883180-G-T
• rs386134159
• NM_002739.5:c.188G>T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 19 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 chrnull-null-null-null is described in UniProt as null.
• 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, 0.992
• 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_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCG	NM_002739.5	c.188G>T	p.Gly63Val	missense_variant	Exon 2 of 18	ENST00000263431.4	NP_002730.1
PRKCG	NM_001316329.2	c.188G>T	p.Gly63Val	missense_variant	Exon 2 of 19		NP_001303258.1
PRKCG	XM_047439092.1	c.-197G>T		5_prime_UTR_variant	Exon 3 of 20		XP_047295048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCG	ENST00000263431.4	c.188G>T	p.Gly63Val	missense_variant	Exon 2 of 18	1	NM_002739.5	ENSP00000263431.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 19, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously as a paternally inherited variant in a patient with dystonia, nonprogressive cerebellar atrophy on brain MRI, dysarthria, slowly progressive gait ataxia, and nystagmus; the father was similarly affected (PMID: 17149711); Published functional studies demonstrate a damaging effect and showed markedly reduced or no PMA-induced membrane translocation (PMID: 29053796); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29053796, 17149711) -

Dec 09, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 18, 2013

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.96		Gain of relative solvent accessibility (P = 0.0479);
MVP		0.97
MPC		3.0
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs386134159; hg19: chr19-54386434;