14-61322295-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006255.5(PRKCH):c.194A>G(p.Lys65Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00098 in 1,612,880 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

PRKCH
NM_006255.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.768

Publications

5 publications found

Variant links:

Genes affected

PRKCH (HGNC:9403): (protein kinase C eta) Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the 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 family members 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 a distinct role in cells. The protein encoded by this gene is one of the PKC family members. It is a calcium-independent and phospholipids-dependent protein kinase. It is predominantly expressed in epithelial tissues and has been shown to reside specifically in the cell nucleus. This protein kinase can regulate keratinocyte differentiation by activating the MAP kinase MAPK13 (p38delta)-activated protein kinase cascade that targets CCAAT/enhancer-binding protein alpha (CEBPA). It is also found to mediate the transcription activation of the transglutaminase 1 (TGM1) gene. Mutations in this gene are associated with susceptibility to cerebral infarction. [provided by RefSeq, Sep 2015]

PRKCH links:

PRKCH-AS1 (HGNC:55588): (PRKCH antisense RNA 1)

PRKCH-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03632921).

BS2

High AC in GnomAd4 at 120 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCH	NM_006255.5 link	c.194A>G	p.Lys65Arg	missense_variant	Exon 1 of 14	ENST00000332981.11	NP_006246.2	P24723-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCH	ENST00000332981.11 link	c.194A>G	p.Lys65Arg	missense_variant	Exon 1 of 14	1	NM_006255.5	ENSP00000329127.5		P24723-1

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

120

AN:

151016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000526

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00149

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000638

AC:

160

AN:

250658

AF XY:

0.000707

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.000796

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00125

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000999

AC:

1461

AN:

1461744

Hom.:

Cov.:

AF XY:

0.000938

AC XY:

682

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000112

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000750

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00125

AC:

1392

AN:

1111968

Other (OTH)

AF:

0.000580

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

177

266

354

443

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000794

AC:

120

AN:

151136

Hom.:

Cov.:

AF XY:

0.000732

AC XY:

AN XY:

73800

show subpopulations

African (AFR)

AF:

0.000218

AC:

AN:

41192

American (AMR)

AF:

0.000526

AC:

AN:

15222

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

4978

South Asian (SAS)

AF:

0.00

AC:

AN:

4764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10442

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00149

AC:

101

AN:

67794

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.000703

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000634

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.00178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.194A>G (p.K65R) alteration is located in exon 1 (coding exon 1) of the PRKCH gene. This alteration results from a A to G substitution at nucleotide position 194, causing the lysine (K) at amino acid position 65 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.8

.;L

PhyloP100

0.77

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.13

Sift

Benign

0.19

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.0030

.;B

Vest4

0.13

MVP

0.70

MPC

0.55

ClinPred

0.014

GERP RS

4.2

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.20

gMVP

0.22

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

14-61322295-A-G

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