19-53882566-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002739.5(PRKCG):c.72C>T(p.Ala24Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.95 in 1,614,066 control chromosomes in the GnomAD database, including 730,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.90 ( 62102 hom., cov: 31)

Exomes 𝑓: 0.96 ( 668192 hom. )

Consequence

PRKCG
NM_002739.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.16

Publications

24 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 19-53882566-C-T is Benign according to our data. Variant chr19-53882566-C-T is described in ClinVar as Benign. ClinVar VariationId is 130037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.16 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCG	NM_002739.5	MANE Select	c.72C>T	p.Ala24Ala	synonymous	Exon 1 of 18	NP_002730.1
	PRKCG	NM_001316329.2		c.72C>T	p.Ala24Ala	synonymous	Exon 1 of 19	NP_001303258.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRKCG	ENST00000263431.4	TSL:1 MANE Select	c.72C>T	p.Ala24Ala	synonymous	Exon 1 of 18	ENSP00000263431.3
PRKCG	ENST00000682028.1		c.72C>T	p.Ala24Ala	synonymous	Exon 1 of 19	ENSP00000507230.1
PRKCG	ENST00000683513.1		c.72C>T	p.Ala24Ala	synonymous	Exon 1 of 17	ENSP00000506809.1

Frequencies

GnomAD3 genomes

AF:

0.898

AC:

136490

AN:

152074

Hom.:

62072

Cov.:

show subpopulations

Gnomad AFR

AF:

0.738

Gnomad AMI

AF:

0.978

Gnomad AMR

AF:

0.942

Gnomad ASJ

AF:

0.946

Gnomad EAS

AF:

0.989

Gnomad SAS

AF:

0.993

Gnomad FIN

AF:

0.963

Gnomad MID

AF:

0.924

Gnomad NFE

AF:

0.957

Gnomad OTH

AF:

0.899

GnomAD2 exomes

AF:

0.950

AC:

238694

AN:

251208

AF XY:

0.955

show subpopulations

Gnomad AFR exome

AF:

0.729

Gnomad AMR exome

AF:

0.964

Gnomad ASJ exome

AF:

0.943

Gnomad EAS exome

AF:

0.989

Gnomad FIN exome

AF:

0.965

Gnomad NFE exome

AF:

0.958

Gnomad OTH exome

AF:

0.951

GnomAD4 exome

AF:

0.955

AC:

1396639

AN:

1461874

Hom.:

668192

Cov.:

AF XY:

0.957

AC XY:

696104

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.731

AC:

24464

AN:

33478

American (AMR)

AF:

0.960

AC:

42950

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.944

AC:

24677

AN:

26134

East Asian (EAS)

AF:

0.994

AC:

39473

AN:

39700

South Asian (SAS)

AF:

0.991

AC:

85513

AN:

86258

European-Finnish (FIN)

AF:

0.963

AC:

51460

AN:

53420

Middle Eastern (MID)

AF:

0.954

AC:

5496

AN:

5762

European-Non Finnish (NFE)

AF:

0.958

AC:

1065398

AN:

1112004

Other (OTH)

AF:

0.947

AC:

57208

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

3859

7719

11578

15438

19297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21614

43228

64842

86456

108070

<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:

0.897

AC:

136579

AN:

152192

Hom.:

62102

Cov.:

AF XY:

0.900

AC XY:

66964

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.738

AC:

30606

AN:

41492

American (AMR)

AF:

0.943

AC:

14421

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.946

AC:

3282

AN:

3470

East Asian (EAS)

AF:

0.989

AC:

5099

AN:

5154

South Asian (SAS)

AF:

0.994

AC:

4802

AN:

4832

European-Finnish (FIN)

AF:

0.963

AC:

10234

AN:

10622

Middle Eastern (MID)

AF:

0.918

AC:

270

AN:

294

European-Non Finnish (NFE)

AF:

0.957

AC:

65070

AN:

68004

Other (OTH)

AF:

0.900

AC:

1903

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

621

1242

1862

2483

3104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

896

1792

2688

3584

4480

<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:

0.939

Hom.:

50539

Bravo

AF:

0.888

Asia WGS

AF:

0.962

AC:

3345

AN:

3478

EpiCase

AF:

0.961

EpiControl

AF:

0.962

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spinocerebellar ataxia type 14

Benign:5

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

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

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Jul 15, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:2

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.

Apr 29, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

-1.2

PromoterAI

-0.013

Neutral

(source)

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over