rs386134169

Variant names:

• chr19-53889905-C-A
• rs386134169
• NM_002739.5:c.417C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_002739.5(PRKCG):​c.417C>A​(p.His139Gln) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H139N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRKCG NM_002739.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0860
• Publications: 4 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 10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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, 0.978
• PP5: Variant 19-53889905-C-A is Pathogenic according to our data. Variant chr19-53889905-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 42171.Status of the report is no_assertion_criteria_provided, 0 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.417C>A	p.His139Gln	missense	Exon 5 of 18	NP_002730.1	P05129-1
	PRKCG	NM_001316329.2		c.417C>A	p.His139Gln	missense	Exon 5 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.417C>A	p.His139Gln	missense	Exon 5 of 18	ENSP00000263431.3	P05129-1
	PRKCG	ENST00000682028.1		c.417C>A	p.His139Gln	missense	Exon 5 of 19	ENSP00000507230.1	A0A804HIU5
	PRKCG	ENST00000683513.1		c.417C>A	p.His139Gln	missense	Exon 5 of 17	ENSP00000506809.1	A0A804HHY0

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1432970 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 710188

African (AFR) AF: 0.00 AC: 0 AN: 32850

American (AMR) AF: 0.00 AC: 0 AN: 40832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25542

East Asian (EAS) AF: 0.00 AC: 0 AN: 38036

South Asian (SAS) AF: 0.00 AC: 0 AN: 82316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098496

Other (OTH) AF: 0.00 AC: 0 AN: 59204

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000717 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Spinocerebellar ataxia type 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		0.086
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.87		Loss of sheet (P = 0.0457)
MVP		0.99
MPC		2.7
ClinPred		0.97	D
GERP RS		2.6
Varity_R		0.93
gMVP		0.99
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386134169; hg19: chr19-54393159;