rs121918513

Positions:

• chr19-53889735-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_002739.5(PRKCG):​c.383G>A​(p.Gly128Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRKCG NM_002739.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.81

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.993
• PP5: Variant 19-53889735-G-A is Pathogenic according to our data. Variant chr19-53889735-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13246.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCG	NM_002739.5	c.383G>A	p.Gly128Asp	missense_variant	4/18	ENST00000263431.4	NP_002730.1
PRKCG	NM_001316329.2	c.383G>A	p.Gly128Asp	missense_variant	4/19		NP_001303258.1
PRKCG	XM_047439092.1	c.-2G>A		5_prime_UTR_variant	5/20		XP_047295048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCG	ENST00000263431.4	c.383G>A	p.Gly128Asp	missense_variant	4/18	1	NM_002739.5	ENSP00000263431	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Spinocerebellar ataxia type 14 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2006	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.010	D
Polyphen		0.43	B
Vest4		0.95
MutPred		0.95		Gain of catalytic residue at G128 (P = 0.0565);
MVP		0.97
MPC		2.5
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.94
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs121918513; hg19: chr19-54392989;