19-53882535-G-A

Variant names:

• chr19-53882535-G-A
• rs758361947
• NM_002739.5:c.41G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_002739.5(PRKCG):​c.41G>A​(p.Gly14Glu) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKCG NM_002739.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

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 Uncertain_significance. Variant got 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13655034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCG	NM_002739.5	c.41G>A	p.Gly14Glu	missense_variant	Exon 1 of 18	ENST00000263431.4	NP_002730.1
PRKCG	NM_001316329.2	c.41G>A	p.Gly14Glu	missense_variant	Exon 1 of 19		NP_001303258.1
PRKCG	XM_047439092.1	c.-322-22G>A		intron_variant	Intron 1 of 19		XP_047295048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCG	ENST00000263431.4	c.41G>A	p.Gly14Glu	missense_variant	Exon 1 of 18	1	NM_002739.5	ENSP00000263431.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250872 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135830

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.41G>A (p.G14E) alteration is located in exon 1 (coding exon 1) of the PRKCG gene. This alteration results from a G to A substitution at nucleotide position 41, causing the glycine (G) at amino acid position 14 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.11	N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.18
Sift	Benign	0.87	T
Sift4G	Benign	0.33	T
Polyphen		0.0010	B
Vest4		0.33
MutPred		0.30		Gain of solvent accessibility (P = 0.0012);
MVP		0.70
MPC		1.8
ClinPred		0.15	T
GERP RS		2.9
Varity_R		0.084
gMVP		0.35

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: rs758361947; hg19: chr19-54385789;