rs2242244

chr19-53900671-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002739.5(PRKCG):c.1497T>C(p.Phe499=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,614,200 control chromosomes in the GnomAD database, including 1,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (198 hom., cov: 32)
  • Exomes 𝑓: 0.015 (804 hom.)
• Consequence: PRKCG NM_002739.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.83

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 19-53900671-T-C is Benign according to our data. Variant chr19-53900671-T-C is described in ClinVar as [Benign]. Clinvar id is 194378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-53900671-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKCG	NM_002739.5	c.1497T>C	p.Phe499=	synonymous_variant	14/18	ENST00000263431.4
PRKCG	NM_001316329.2	c.1497T>C	p.Phe499=	synonymous_variant	14/19
PRKCG	XM_047439092.1	c.1113T>C	p.Phe371=	synonymous_variant	15/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCG	ENST00000263431.4	c.1497T>C	p.Phe499=	synonymous_variant	14/18	1	NM_002739.5	P1

Frequencies

GnomAD3 genomes AF: 0.0332 AC: 5046 AN: 152192 Hom.: 198 Cov.: 32

Gnomad AFR AF: 0.0788

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00548

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0301 AC: 7578 AN: 251482 Hom.: 276 AF XY: 0.0270 AC XY: 3672 AN XY: 135914

Gnomad AFR exome AF: 0.0807

Gnomad AMR exome AF: 0.0504

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.0428

Gnomad FIN exome AF: 0.00346

Gnomad NFE exome AF: 0.00640

Gnomad OTH exome AF: 0.0246

GnomAD4 exome AF: 0.0151 AC: 22079 AN: 1461890 Hom.: 804 Cov.: 33 AF XY: 0.0153 AC XY: 11127 AN XY: 727248

Gnomad4 AFR exome AF: 0.0786

Gnomad4 AMR exome AF: 0.0465

Gnomad4 ASJ exome AF: 0.00631

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.0419

Gnomad4 FIN exome AF: 0.00384

Gnomad4 NFE exome AF: 0.00533

Gnomad4 OTH exome AF: 0.0218

GnomAD4 genome AF: 0.0332 AC: 5056 AN: 152310 Hom.: 198 Cov.: 32 AF XY: 0.0338 AC XY: 2520 AN XY: 74478

Gnomad4 AFR AF: 0.0789

Gnomad4 AMR AF: 0.0264

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.0503

Gnomad4 FIN AF: 0.00282

Gnomad4 NFE AF: 0.00548

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0130 Hom.: 57

Bravo AF: 0.0376

Asia WGS AF: 0.104 AC: 359 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00616

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 08, 2014

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

Spinocerebellar ataxia type 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.98
Dann	Benign	0.61

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: rs2242244; hg19: chr19-54403925; COSMIC: COSV54725623;