rs2230500

Positions:

• chr14-61457521-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000332981.11(PRKCH):​c.1120G>A​(p.Val374Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,614,004 control chromosomes in the GnomAD database, including 1,583 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.019 (190 hom., cov: 32)
  • Exomes 𝑓: 0.018 (1393 hom.)
• Consequence: PRKCH ENST00000332981.11 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 2.13

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019232929).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCH	NM_006255.5	c.1120G>A	p.Val374Ile	missense_variant	9/14	ENST00000332981.11	NP_006246.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCH	ENST00000332981.11	c.1120G>A	p.Val374Ile	missense_variant	9/14	1	NM_006255.5	ENSP00000329127	P1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2851 AN: 152116 Hom.: 188 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0308 AC: 7738 AN: 251296 Hom.: 678 AF XY: 0.0299 AC XY: 4064 AN XY: 135806

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00613

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.268

Gnomad SAS exome AF: 0.0123

Gnomad FIN exome AF: 0.0357

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0180 AC: 26311 AN: 1461768 Hom.: 1393 Cov.: 32 AF XY: 0.0177 AC XY: 12888 AN XY: 727184

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00653

Gnomad4 ASJ exome AF: 0.00911

Gnomad4 EAS exome AF: 0.242

Gnomad4 SAS exome AF: 0.0128

Gnomad4 FIN exome AF: 0.0322

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.0258

GnomAD4 genome AF: 0.0187 AC: 2854 AN: 152236 Hom.: 190 Cov.: 32 AF XY: 0.0211 AC XY: 1568 AN XY: 74428

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.00922

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.258

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.0327

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0186 Hom.: 279

Bravo AF: 0.0170

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00837 AC: 72

ExAC AF: 0.0294 AC: 3570

Asia WGS AF: 0.135 AC: 468 AN: 3478

EpiCase AF: 0.00960

EpiControl AF: 0.00865

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Cerebral infarction, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.079	T;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.55	T;T;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	N;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.22	N;N;N
REVEL	Benign	0.064
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.056
MPC		0.41
ClinPred		0.0051	T
GERP RS		4.6
Varity_R		0.062
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs2230500; hg19: chr14-61924239; COSMIC: COSV60646806; COSMIC: COSV60646806;