chr19-53889735-G-A

Variant names:

• chr19-53889735-G-A
• rs121918513
• NM_002739.5:c.383G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM1 PM2 PP2 PP3_Strong PP5_Moderate

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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV005907087: Published functional studies demonstrate a damaging effect and show that this variant is associated with abnormal aggregation within cells, decreased colocalization with Golgi complex, decreased phosphorylation at key sites for PKC activation, and increased cell death (PMID:15964845, 35760954)". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G128R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRKCG NM_002739.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.81
• Publications: 18 publications found

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]

PRKCG Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 14

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005907087: Published functional studies demonstrate a damaging effect and show that this variant is associated with abnormal aggregation within cells, decreased colocalization with Golgi complex, decreased phosphorylation at key sites for PKC activation, and increased cell death (PMID: 15964845, 35760954)
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_002739.5
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.993
• PP5: Variant 19-53889735-G-A is Pathogenic according to our data. Variant chr19-53889735-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13246.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002739.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCG	NM_002739.5	MANE Select	c.383G>A	p.Gly128Asp	missense	Exon 4 of 18	NP_002730.1	P05129-1
	PRKCG	NM_001316329.2		c.383G>A	p.Gly128Asp	missense	Exon 4 of 19	NP_001303258.1	A0A804HIU5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCG	ENST00000263431.4	TSL:1 MANE Select	c.383G>A	p.Gly128Asp	missense	Exon 4 of 18	ENSP00000263431.3	P05129-1
	PRKCG	ENST00000682028.1		c.383G>A	p.Gly128Asp	missense	Exon 4 of 19	ENSP00000507230.1	A0A804HIU5
	PRKCG	ENST00000683513.1		c.383G>A	p.Gly128Asp	missense	Exon 4 of 17	ENSP00000506809.1	A0A804HHY0

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000717 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Spinocerebellar ataxia type 14 (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.8
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918513; hg19: chr19-54392989;