rs115832790

Positions:

• chr19-53891782-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP6_Moderate BS2

The NM_002739.5(PRKCG):​c.638G>A​(p.Arg213Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,614,078 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (3 hom.)
• Consequence: PRKCG NM_002739.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.35

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• 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.
• BP6: Variant 19-53891782-G-A is Benign according to our data. Variant chr19-53891782-G-A is described in ClinVar as [Benign]. Clinvar id is 586454.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCG	NM_002739.5	c.638G>A	p.Arg213Gln	missense_variant	6/18	ENST00000263431.4	NP_002730.1
PRKCG	NM_001316329.2	c.638G>A	p.Arg213Gln	missense_variant	6/19		NP_001303258.1
PRKCG	XM_047439092.1	c.254G>A	p.Arg85Gln	missense_variant	7/20		XP_047295048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCG	ENST00000263431.4	c.638G>A	p.Arg213Gln	missense_variant	6/18	1	NM_002739.5	ENSP00000263431.3

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000493 AC: 124 AN: 251494 Hom.: 1 AF XY: 0.000471 AC XY: 64 AN XY: 135922

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00356

Gnomad NFE exome AF: 0.000360

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000287 AC: 419 AN: 1461860 Hom.: 3 Cov.: 55 AF XY: 0.000272 AC XY: 198 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.000235

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000539 AC: 82 AN: 152218 Hom.: 0 Cov.: 31 AF XY: 0.000739 AC XY: 55 AN XY: 74424

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00472

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000303 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	.;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	.;N
REVEL	Benign	0.069
Sift	Benign	0.13	.;T
Sift4G	Uncertain	0.056	T;T
Polyphen		0.0030	.;B
Vest4		0.17
MVP		0.76
MPC		0.55
ClinPred		0.024	T
GERP RS		4.1
Varity_R		0.10
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs115832790; hg19: chr19-54395036; COSMIC: COSV54735169; COSMIC: COSV54735169;