19-53900671-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002739.5(PRKCG):c.1497T>C(p.Phe499Phe) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.83

Publications

11 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 194378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
PRKCG	NM_002739.5 link	c.1497T>C	p.Phe499Phe	synonymous_variant	Exon 14 of 18	ENST00000263431.4	NP_002730.1	P05129-1
PRKCG	NM_001316329.2 link	c.1497T>C	p.Phe499Phe	synonymous_variant	Exon 14 of 19		NP_001303258.1	P05129B7Z3W6B2R5T1A0A804HIU5
PRKCG	XM_047439092.1 link	c.1113T>C	p.Phe371Phe	synonymous_variant	Exon 15 of 20		XP_047295048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCG	ENST00000263431.4 link	c.1497T>C	p.Phe499Phe	synonymous_variant	Exon 14 of 18	1	NM_002739.5	ENSP00000263431.3		P05129-1

Frequencies

GnomAD3 genomes

AF:

0.0332

AC:

5046

AN:

152192

Hom.:

198

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0301

AC:

7578

AN:

251482

AF XY:

0.0270

show subpopulations

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 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.:

AF XY:

0.0153

AC XY:

11127

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0786

AC:

2633

AN:

33480

American (AMR)

AF:

0.0465

AC:

2079

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00631

AC:

165

AN:

26136

East Asian (EAS)

AF:

0.151

AC:

5983

AN:

39700

South Asian (SAS)

AF:

0.0419

AC:

3618

AN:

86258

European-Finnish (FIN)

AF:

0.00384

AC:

205

AN:

53416

Middle Eastern (MID)

AF:

0.0264

AC:

152

AN:

5768

European-Non Finnish (NFE)

AF:

0.00533

AC:

5928

AN:

1112012

Other (OTH)

AF:

0.0218

AC:

1316

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1719

3437

5156

6874

8593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

374

748

1122

1496

1870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0332

AC:

5056

AN:

152310

Hom.:

198

Cov.:

AF XY:

0.0338

AC XY:

2520

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0789

AC:

3280

AN:

41564

American (AMR)

AF:

0.0264

AC:

403

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.121

AC:

627

AN:

5178

South Asian (SAS)

AF:

0.0503

AC:

243

AN:

4830

European-Finnish (FIN)

AF:

0.00282

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00548

AC:

373

AN:

68034

Other (OTH)

AF:

0.0327

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

243

486

729

972

1215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0199

Hom.:

163

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 08, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spinocerebellar ataxia type 14

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.61

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over