19-53891711-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.567T>C(p.Asn189Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,613,570 control chromosomes in the GnomAD database, including 135,641 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10658 hom., cov: 31)

Exomes 𝑓: 0.41 ( 124983 hom. )

Consequence

PRKCG
NM_002739.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

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:

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=-0.53).

BP6

Variant 19-53891711-T-C is Benign according to our data. Variant chr19-53891711-T-C is described in ClinVar as Benign. ClinVar VariationId is 130036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.335 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCG	NM_002739.5 link	c.567T>C	p.Asn189Asn	synonymous_variant	Exon 6 of 18	ENST00000263431.4	NP_002730.1	P05129-1
PRKCG	NM_001316329.2 link	c.567T>C	p.Asn189Asn	synonymous_variant	Exon 6 of 19		NP_001303258.1	P05129B7Z3W6B2R5T1A0A804HIU5
PRKCG	XM_047439092.1 link	c.183T>C	p.Asn61Asn	synonymous_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>C	p.Asn189Asn	synonymous_variant	Exon 6 of 18	1	NM_002739.5	ENSP00000263431.3		P05129-1

Frequencies

GnomAD3 genomes

AF:

0.362

AC:

54960

AN:

151852

Hom.:

10655

Cov.:

show subpopulations

Gnomad AFR

AF:

0.214

Gnomad AMI

AF:

0.500

Gnomad AMR

AF:

0.427

Gnomad ASJ

AF:

0.445

Gnomad EAS

AF:

0.301

Gnomad SAS

AF:

0.422

Gnomad FIN

AF:

0.458

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.416

Gnomad OTH

AF:

0.373

GnomAD2 exomes

AF:

0.406

AC:

102157

AN:

251486

AF XY:

0.409

show subpopulations

Gnomad AFR exome

AF:

0.217

Gnomad AMR exome

AF:

0.470

Gnomad ASJ exome

AF:

0.438

Gnomad EAS exome

AF:

0.300

Gnomad FIN exome

AF:

0.454

Gnomad NFE exome

AF:

0.412

Gnomad OTH exome

AF:

0.403

GnomAD4 exome

AF:

0.411

AC:

600911

AN:

1461600

Hom.:

124983

Cov.:

AF XY:

0.412

AC XY:

299808

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.210

AC:

7032

AN:

33470

American (AMR)

AF:

0.463

AC:

20720

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.438

AC:

11442

AN:

26132

East Asian (EAS)

AF:

0.289

AC:

11489

AN:

39696

South Asian (SAS)

AF:

0.432

AC:

37303

AN:

86258

European-Finnish (FIN)

AF:

0.448

AC:

23906

AN:

53406

Middle Eastern (MID)

AF:

0.375

AC:

2164

AN:

5768

European-Non Finnish (NFE)

AF:

0.416

AC:

462574

AN:

1111768

Other (OTH)

AF:

0.402

AC:

24281

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

22562

45124

67687

90249

112811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14198

28396

42594

56792

70990

<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:

0.362

AC:

54976

AN:

151970

Hom.:

10658

Cov.:

AF XY:

0.365

AC XY:

27074

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.214

AC:

8875

AN:

41474

American (AMR)

AF:

0.427

AC:

6512

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.445

AC:

1540

AN:

3464

East Asian (EAS)

AF:

0.300

AC:

1545

AN:

5142

South Asian (SAS)

AF:

0.422

AC:

2032

AN:

4810

European-Finnish (FIN)

AF:

0.458

AC:

4834

AN:

10564

Middle Eastern (MID)

AF:

0.387

AC:

113

AN:

292

European-Non Finnish (NFE)

AF:

0.416

AC:

28277

AN:

67960

Other (OTH)

AF:

0.376

AC:

793

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1704

3407

5111

6814

8518

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

538

1076

1614

2152

2690

<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:

0.373

Hom.:

13251

Bravo

AF:

0.352

Asia WGS

AF:

0.359

AC:

1251

AN:

3478

EpiCase

AF:

0.420

EpiControl

AF:

0.411

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spinocerebellar ataxia type 14

Benign:4

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 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. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

4.4

(source)

DANN

Benign

0.49

PhyloP100

-0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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