dbSNP rs3745406: PRKCG:p.Asn189Lys (chr19-53891711-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_002739.5(PRKCG):c.567T>A(p.Asn189Lys) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N189S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

PRKCG
NM_002739.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.335

Publications

27 publications found

Variant links:

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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

PRKCG links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCG	NM_002739.5 link	c.567T>A	p.Asn189Lys	missense_variant	Exon 6 of 18	ENST00000263431.4	NP_002730.1	P05129-1
PRKCG	NM_001316329.2 link	c.567T>A	p.Asn189Lys	missense_variant	Exon 6 of 19		NP_001303258.1	P05129B7Z3W6B2R5T1A0A804HIU5
PRKCG	XM_047439092.1 link	c.183T>A	p.Asn61Lys	missense_variant	Exon 7 of 20		XP_047295048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCG	ENST00000263431.4 link	c.567T>A	p.Asn189Lys	missense_variant	Exon 6 of 18	1	NM_002739.5	ENSP00000263431.3		P05129-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251486

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

.;D

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.82

T;D

M_CAP

Benign

0.080

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.0

.;M

PhyloP100

-0.34

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.4

.;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0020

.;D

Sift4G

Benign

0.068

T;T

Polyphen

1.0

.;D

Vest4

0.75

MutPred

0.63

.;Gain of ubiquitination at N189 (P = 0.0048);

MVP

0.86

MPC

1.4

ClinPred

0.98

GERP RS

-1.7

Varity_R

0.70

gMVP

0.88

Mutation Taster

=20/80

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.30

Position offset: 2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over