19-53906410-G-T

Variant names:

• chr19-53906410-G-T
• rs1177582167
• NM_002739.5:c.1858G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_002739.5(PRKCG):​c.1858G>T​(p.Glu620*) variant causes a stop gained 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRKCG NM_002739.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.89
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.1858G>T	p.Glu620*	stop_gained	Exon 17 of 18	NP_002730.1	P05129-1
	PRKCG	NM_001316329.2		c.1858G>T	p.Glu620*	stop_gained	Exon 17 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.1858G>T	p.Glu620*	stop_gained	Exon 17 of 18	ENSP00000263431.3	P05129-1
	PRKCG	ENST00000682028.1		c.1858G>T	p.Glu620*	stop_gained	Exon 17 of 19	ENSP00000507230.1	A0A804HIU5
	PRKCG	ENST00000683513.1		c.1750G>T	p.Glu584*	stop_gained	Exon 16 of 17	ENSP00000506809.1	A0A804HHY0

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1419640 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 702310

African (AFR) AF: 0.00 AC: 0 AN: 32436

American (AMR) AF: 0.00 AC: 0 AN: 38884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25326

East Asian (EAS) AF: 0.00 AC: 0 AN: 37418

South Asian (SAS) AF: 0.00 AC: 0 AN: 81248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089718

Other (OTH) AF: 0.00 AC: 0 AN: 58674

GnomAD4 genome Cov.: 29

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		7.9
Vest4		0.79
GERP RS		3.9
Mutation Taster		=5/195	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1177582167; hg19: chr19-54409664;